insulin resistance

Treatment Approach to Patients With Severe Insulin Resistance

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In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin.

An increasing number of patients have severe insulin resistance and require large doses of insulin. Managing patients with severe insulin resistance is challenging because it is difficult to achieve good glycemic control using conventional treatment approaches (1). Moreover, weight gain, hypoglycemia, regimen complexity, and cost are frequent concerns as insulin doses escalate.

Insulin resistance is characterized by an impaired response to either endogenous or exogenous insulin (2). Although insulin resistance is a common feature of type 2 diabetes, cases of severe insulin resistance remain relatively uncommon but are likely increasing as the prevalence of diabetes and obesity surges. The degree of insulin resistance can be measured using the euglyemic insulin clamp technique, but this is not a clinically useful method of determining whether a patient has severe insulin resistance in practice (3). The most widely reported and clinically useful definitions of severe insulin resistance are based on exogenous insulin requirements using either the number of units per kilogram of body weight per day or the total daily dose (1). Patients who require >1 unit/kg/day are considered to have insulin resistance, and those requiring >2 units/kg/day have severe resistance (3). Alternatively, a total daily insulin dose of >200 units is commonly considered to be evidence of severe insulin resistance. Large total daily dose requirements create practical problems with regard to insulin delivery because 1) a large volume of standard U-100 insulin can be painful to administer and 2) the onset and duration of insulin activity can be altered with high-volume doses (4).

Evaluating Patients

There are several known causes of severe insulin resistance, including several rare disorders and genetic conditions (Table 1) (3). Several medications are known to contribute to insulin resistance, including glucocorticoids, protease inhibitors, atypical antipsychotics, and calcineurin inhibitors. In patients with severe insulin resistance, an effort should be made to discontinue such agents or switch to alternative medications if possible (5).

TABLE 1.

Causes of Severe Insulin Resistance (3)

Syndromes of severe insulin resistanceType A, due to defects in the insulin receptor geneType B, due to insulin receptor antibodiesType C, cause unknown (also known as HAIR-AN [Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans] syndrome) 
MedicationsGlucocorticoidsAtypical antipsychoticsCalcineurin inhibitorsProtease inhibitorsOral contraceptives 
Endocrine disordersAcromegalyGlucagonomaThyrotoxicosisCushing’s syndromePheochromocytoma 
Anti-insulin antibodies 
HIV-associated lipodystrophy 
Physiological causesSevere stressTraumaSepsisSurgeryDiabetic ketoacidosisPregnancyPuberty 
PseudoresistancePoor administration techniqueIncorrect storage of insulinMalingering for secondary gain 

Poor medication-taking behaviors or “pseudoresistance” should be ruled out before modifying or intensifying therapy. Pseudoresistance may be the result of nonadherence, poor injection technique, improper insulin storage, or malingering for secondary gain. Pseudoresistance can be ruled out by conducting a modified insulin tolerance test (3). During such a test, patients are administered a witnessed dose of short-acting insulin in the clinic, and their blood glucose is monitored every 30 minutes for a period of 4–8 hours. Patients should be fasting for the test and should have a blood glucose level >150 mg/dL. A witnessed insulin dose approximately equal to what an average person with diabetes might require (insulin dose [units] = blood glucose [mg/dL] – 100 / (1,500 / weight [kg] × 1.0)] should be given. If there is not an appropriate drop in blood glucose within 4 hours, a second dose should be given. If normoglycemia or hypoglycemia is not achieved after either dose, the test confirms that a patient likely has severe insulin resistance.

Pharmacological Treatment Options

There are currently no guidelines or consensus statements describing how best to treat patients with severe insulin resistance. Until recently, insulin was the only therapy available to treat those with severe insulin resistance. Despite the use of high doses of insulin, however, many patients do not reach their glycemic targets and are hampered by undesirable adverse effects such as hypoglycemia and weight gain. To mitigate some of these challenges, several new therapies have emerged and can be used in combination with insulin.

Concentrated Insulin Products

Concentrated insulin products can help improve the delivery of insulin when very large doses are needed. U-500 insulin is five times more concentrated than standard U-100 insulin and is considered the cornerstone of therapy for most patients with severe insulin resistance (6). When daily insulin doses exceed 200 units/day, the volume of U-100 insulin needed makes insulin delivery challenging. Available insulin syringes can deliver a maximum of 100 units, and insulin pen devices can deliver only 60–80 units per injection. In addition, the administration of doses >1 mL in volume can be painful and may alter insulin absorption (7).

Two new concentrated insulin pen products are now available in the United States—U-200 insulin lispro and U-300 insulin glargine. There is no reported experience using these new concentrated insulin products in patients with severe insulin resistance, and clinical trials comparing these products to U-500 insulin have not been conducted. Although they are two to three times more concentrated than U-100 insulin, U-300 insulin glargine and U-200 insulin lispro can only deliver a maximum of 80 and 60 units per injection, respectively. They do offer the theoretical advantage of providing a dose of insulin in a smaller injection volume than would be required with U-100 (8,9).

Similar to U-100 regular insulin, the onset of activity for U-500 regular insulin is ∼30–45 minutes. However, the time to peak activity (4–6 hours) and duration of action (12–14 hours) for U-500 is most similar to NPH insulin (6).

In several crossover studies in which patients with severe insulin resistance were switched from U-100 insulin products to U-500 regular insulin, significant improvements in glycemic control have been observed (10–18). An analysis of nine studies (n = 310 patients) found that U-500 reduced mean A1C by 1.59% (95% CI 1.26–1.92) in patients who previously used a multiple daily injection (MDI) regimen with various U-100 insulin products. At baseline, these patients had an A1C between 9.1 and 11.3% and a total daily insulin requirement of 219–391 units. They were followed for 6–36 months. Weight gain was a substantial problem, with a mean increase of 4.4 kg (95% CI 2.4–6.4) in body weight. The mean total daily insulin dose increased by 52 units (95% CI 20–84) (19). U-500 insulin delivered by continuous subcutaneous insulin infusion (CSII) is a potential option. In one study, U-500 delivered via CSII reduced mean A1C by 1.1% (P = 0.026) in a cohort of patients with severe insulin resistance who were switched from a variety of insulin regimens, including U-500 insulin via MDI (20).

The risk of severe hypoglycemia does not appear to increase when patients are switched from U-100 to U-500 insulin (6,19). However, some studies have reported an increase in mild hypoglycemic events, defined as symptomatic episodes that did not require assistance (13,15). One retrospective study reported an increase in the frequency of mild hypoglycemic episodes only during the first 3 months after transitioning to U-500 insulin (13).

When transitioning a patient from U-100 to U-500 insulin, the dose and dosing frequency should be determined based on the patient’s current A1C and total daily insulin dose. Dosing algorithms have not yet been prospectively evaluated (Figure 1); nonetheless, they have been widely used. In general, U-500 should be given at least 30 minutes before a meal. One of the biggest drawbacks to using U-500 insulin is the potential for dosing errors that can lead to severe hypoglycemia, coma, or death. Clear communications between the prescriber, pharmacist, and patient are crucial. When prescribing and dispensing U-500 regular insulin, the dose should be expressed in both units and volume (mL) to be administered. To minimize the risk of errors, a 0.5–1 mL tuberculin syringe with a 29-gauge or higher needle should be used to administer each dose—not a U-100 insulin syringe (6,21).

U-500 regular insulin initial dosing recommendations (6,55).

Metformin

The American Diabetes Association recommends metformin as the initial pharmacological option for most people with type 2 diabetes. It has a strong record of safety and efficacy, as well as a favorable effect on weight (22). Although it is common practice to combine metformin with insulin, metformin use has not been specifically evaluated in the setting of severe insulin resistance.

In most studies of U-500 regular insulin, patients have been permitted to continue metformin use (6,23,24). In patients who do not have severe insulin resistance, metformin use reduces insulin requirements and has a positive impact on glycemic control and weight. A meta-analysis of 26 randomized, controlled trials assessed the effects of metformin plus insulin versus insulin alone. Metformin combined with insulin resulted in a significant reduction in A1C (mean difference –0.60%, P <0.001) and lower insulin requirements (mean difference –18.9 units/day, P <0.001) when compared to insulin therapy alone. Moreover, weight gain was mitigated with combination therapy (mean difference –1.68 kg, P <0.001). The largest study conducted to date combining metformin with insulin therapy is the HOME (Hyperinsulinemia: the Outcome of its Metabolic Effects) study (25). The HOME study randomized 390 patients with type 2 diabetes currently using basal-bolus insulin regimens to either metformin titrated to 850 mg three times daily or placebo. At baseline, patients’ mean total daily insulin dose was ∼70 units, mean A1C was 7.8%, and mean body weight was 86 kg. At the end of the 16-week treatment period, those in the metformin group had a significant reduction in A1C of 0.9% compared to 0.3% in the placebo group (P <0.0001). Total mean daily insulin requirements were reduced by ∼10% (7.2 units) from baseline in the metformin group (P <0.0001), along with a small but statistically significant reduction in weight of 0.4 kg (P <0.0001).

Metformin is known to cause gastrointestinal (GI) side effects, which can lead to discontinuation of therapy (26). This typically manifests as diarrhea and less commonly as nausea or abdominal cramping (22,26). One option to mitigate these effects is to use the extended-release formulation of metformin, which has been shown to reduce the frequency of any GI side effects, including diarrhea (27).

Use of metformin in the setting of mild to moderate renal impairment is controversial. The potential risk of lactic acidosis appears to be negligible in the absence of other risk factors. Current U.S. Food and Drug Administration (FDA)-approved labeling for metformin still recommends against using metformin in men with a serum creatinine ≥1.5 mg/dL and in women with a serum creatinine ≥1.4 mg/dL (28). However, a Cochrane review including 347 studies concluded that the incidence of lactic acidosis was 4.3 cases per 100,000 patient-years in those treated with metformin compared to 5.4 cases per 100,000 patients for those not treated with metformin (29). Several organizations, including the American Geriatric Society, and the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines now advocate for continued metformin use as long as a patient’s estimated glomerular filtration rate is >30 mL/min (30,31).

Glucagon-Like Peptide 1 Receptor Agonists

Glucagon-like peptide 1 (GLP-1) receptor agonists stimulate the GLP-1 receptors in the pancreas and thereby increase insulin release and inhibit glucagon secretion, but only in the presence of elevated blood glucose (32). A recent meta-analysis of 15 studies showed that a GLP-1 receptor agonist combined with basal insulin was superior to basal-bolus insulin combinations in patients with type 2 diabetes (33). The GLP-1 receptor agonist–basal insulin combination led to significantly improved glycemic control and reduced body weight without increasing the risk of hypoglycemia when compared to basal-bolus insulin alone. These features have sparked interest in using GLP-1 receptor agonists in patients with severe insulin resistance (23,24).

In one recent, prospective, open-label study, 37 obese patients using basal-bolus insulin with total daily insulin requirements >100 units/day and a baseline A1C >6.5% were randomized to receive either liraglutide titrated to 1.8 mg/day or continued uptitration of their insulin doses (24). Seventeen patients were using U-500 insulin at baseline. Mean baseline A1C (7.8%) was similar in the two groups, but the mean total daily insulin dose was greater in the liraglutide group (199 vs. 171 units/day) and baseline weight was greater in the insulin treatment group (112 vs. 131 kg). At 6 months, both groups had statistically significant improvements in A1C compared to baseline. However, the A1C reduction was significantly greater in the liraglutide treatment group than in the insulin treatment group (mean A1C at 6 months 7.14 vs. 7.40%, P = 0.047). Moreover, time spent in the euglycemic range (blood glucose 70–180 mg/dL) based on continuous glucose monitoring increased from 57% of the time at baseline to 75% of the time at 6 months in the liraglutide group. The liraglutide group experienced significant weight loss (–5.3 kg, P <0.001) compared to a nonsignificant weight gain in the insulin-only treatment group (0.4 kg, P = 0.595). The mean total daily insulin dose in the liraglutide group dropped by 34% from 199 to 132 units (P <0.0001), whereas insulin requirements in the insulin titration group remained relatively unchanged, with a nonsignificant 4% increase from 171 to 178 units (P = 0.453). Hypoglycemia (blood glucose <70 mg/dL) based on continuous glucose monitoring was similar in both groups (<5% of the time) at baseline and 6-month follow-up. There were no episodes of severe hypoglycemia requiring assistance in any subjects during the study.

In another small, open-label, prospective study, 30 obese patients with type 2 diabetes treated with U-100 insulin and requiring >200 units/day of insulin were randomized to U-500 insulin or U-500 plus exenatide titrated to 10 μg twice daily (34). All patients in both treatment groups also received metformin in doses of 1,700–2,550 mg/day. Baseline A1C (9.2 vs. 8.7%), weight (118 vs. 119 kg), and total daily insulin dose (237 vs. 253 units) were reasonably similar in the two groups. After 6 months of treatment, there were significant improvements in glycemic control in both groups compared to baseline, but there was no difference in the between-group comparison (P = 0.80). There was a slight but nonsignificant mean weight loss in the exenatide group (–0.4 kg) and a slight but nonsignificant mean weight gain (3.6 kg) in the U-500 insulin-only group compared to baseline, with a between-group difference (4.0 kg) that was not statistically different at 6 months (P = 0.07). Similarly, total daily insulin doses were slightly lower in the U-500 insulin (–7 units/day) and exenatide (–27 units) treatment groups at 6 months compared to baseline, but the within- and between-group differences were not statistically significant. None of the patients experienced severe hypoglycemia requiring assistance, and mild symptomatic episodes were more frequent in the exenatide treatment group (50 vs. 11 episodes, P <0.001) over the 6-month treatment period.

A small, retrospective, observational study analyzed the effects of adding liraglutide to U-500 insulin in 15 obese patients with severe insulin resistance (23). The cohort’s mean baseline A1C was 8.5%, total daily insulin dose was 192 units, and weight was 137 kg. After 12 weeks of liraglutide treatment at a dose of 1.2 or 1.8 mg/day, there was a significant mean reduction in A1C (1.4%, P = 0.0001), total daily insulin dose (44 units, P = 0.0001), and weight (5.1 kg, P = 0.0001). Hypoglycemia, defined as blood glucose <70 mg/dL, occurred in eight patients, but there were no severe episodes requiring assistance.

Nausea and vomiting are the most common adverse effects associated with GLP-1 receptor agonist use, but they are often transient. It is a dose-dependent phenomenon, and the incidence varies among the FDA-approved products in this class (35).

Although combination therapy with GLP-1 receptor agonists and basal-bolus insulin is not approved by the FDA, there are several potential benefits when adding these agents to U-100 insulin, including improvement in glycemic control, weight loss, and reduced insulin requirements (24). Some patients may be able to discontinue prandial insulin use. However, it remains unclear whether combining U-500 insulin with a GLP-1 receptor agonist is an effective or cost-effective strategy. More studies are needed comparing GLP-1 receptor agonists to U-500 regular insulin to define which patients with severe insulin resistance would benefit most from these therapies.

Sodium-Glucose Cotransporter 2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase the excretion of urinary glucose, thereby reducing plasma glucose concentrations independent of the presence of insulin (36). These medications have been shown to reduce body weight, and this is one of the features that has prompted studies in obese patients treated with insulin.

A 52-week, double-blind, placebo-controlled trial of 563 obese patients with uncontrolled type 2 diabetes on a total daily insulin dose >60 units were randomized to receive once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo (37). During weeks 19–40 of this study, insulin doses were titrated to achieve specified glucose targets. The mean A1C of study subjects at baseline was 8.3%, and patients had an average daily insulin dose of 92 units. At 18 weeks, A1C was reduced by 0.4% in the empagliflozin 10 mg group and by 0.5% in the 25 mg group compared to placebo (P <0.001), and these improvements in glycemic control were largely sustained at 52 weeks in both treatment groups. When compared to insulin requirements in the placebo group, the mean total daily insulin dose in the empagliflozin 10 mg group was 8.8 units lower (P = 0.004) and in the 25 mg group was 11.2 units lower (P <0.001). Patients who received empagliflozin lost ∼2 kg of weight compared to a 0.4-kg weight gain in the placebo group (P <0.001). Objectively confirmed hypoglycemia during the 52-week study occurred in a similar percentage of patients in the empagliflozin 10 mg (51.1%), empagliflozin 25 mg (57.7%), and placebo (58.0%) groups. Three patients each in the placebo and empagliflozin 10 mg groups and 1 patient in the empagliflozin 25 mg group had severe hypoglycemia requiring assistance.

SGLT2 inhibitors are known to increase the risk of urinary tract and genital mycotic infections, particularly in women with a history of these infections (38). Some patients experience orthostatic hypotension and changes in renal function secondary to the osmotic diuresis. Thus, in patients with severe insulin resistance who have very poor glycemic control, SGLT2 inhibitors are not the best choice because these patients are already at higher risk for dehydration and developing genitourinary tract infections.

Available data suggest that SGLT2 inhibitors, when combined with insulin therapy, may lead to modest improvements in glycemic control and modest weight loss without increasing the risk of hypoglycemia. However, given the lack of data regarding the benefits of SGLT2 inhibitors in patients with severe insulin resistance, it is premature to recommend their use.

Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors prolong the activity of endogenous GLP-1 and glucose insulinotropic polypeptide by preventing their breakdown and potentiating their actions. On the surface, DPP-4 inhibitors, which are taken orally, would appear to be an attractive alternative to GLP-1 receptor agonists for the management of patients with severe insulin resistance. Indeed, all FDA-approved DPP-4 inhibitors have been studied in combination with insulin. However, none have been studied in patients with severe insulin resistance (39). When combined with insulin, DPP-4 inhibitors produce roughly similar reductions in mean A1C of 0.4–0.6% over a period of 24–52 weeks (40–43). However, unlike treatment with GLP-1 receptor agonists, DPP-4 inhibitors, when combined with insulin, do not promote weight loss or reduce total daily insulin requirements. Although DPP-4 inhibitors are well tolerated and typically do not increase the risk of hypoglycemia, their role in the management of patients with severe insulin resistance is questionable (22,39).

Pramlintide

Pramlintide is a synthetic analog of amylin, a neuroendocrine hormone that is cosecreted with insulin from pancreatic β-cells. It is effective as an adjunct to insulin therapy in patients with type 1 or type 2 diabetes by reducing postprandial glucose excursions (44). None of the studies conducted to date have specifically examined the benefits of pramlintide in patients with severe insulin resistance, but two studies in patients with poorly controlled type 2 diabetes provide some insights. Patients in these placebo-controlled studies received pramlintide in doses ranging from 90 to 300 µg/day (45,46). The mean baseline A1C was ∼9% in both studies, and the total daily insulin dose was 60–70 units. After 52 weeks, there was a statistically significant reduction in A1C of 0.6–0.7% and in weight of 1.4–1.5 kg. In one study, insulin total daily dose requirements increased in all treatment groups but to a lesser degree in the pramlintide groups (46).

Severe hypoglycemia requiring assistance may occur during the first 4 weeks of treatment with pramlintide, but beyond the initial treatment period, the risk appears to be similar to placebo (45). To mitigate the potential risk of severe hypoglycemia, the manufacturer recommends reducing prandial insulin doses when initiating pramlintide, and this practice also would be prudent in patients with severe insulin resistance (44). Nausea is a common adverse effect associated with pramlintide use (45,46), but it does not appear to be dose dependent and is typically transient, subsiding after 4–8 weeks of therapy.

Pramlintide produces modest improvements in glycemic control and weight without significantly increasing the risk of hypoglycemia. Its major drawback is frequent subcutaneous administration; it must be taken two or three times daily before meals. In the setting of severe insulin resistance, pramlintide use might result in reduced insulin requirements and significantly greater weight loss, but data are lacking. GLP-1 receptor agonists appear to be a better option to achieve these goals.

Thiazolidinediones

Thiazolidinediones (TZDs) improve insulin sensitivity by increasing insulin-dependent glucose disposal and decreasing hepatic glucose output. Given their mechanism of action, TZDs commonly have been combined with insulin in practice. TZDs have not been evaluated specifically in the setting of severe insulin resistance, but a few studies have examined their use in combination with insulin (47). A double-blind trial of 222 patients with uncontrolled type 2 diabetes (mean A1C of 8.5%) requiring insulin (mean total daily dose of 56 units/day) were randomized to pioglitazone (titrated to 45 mg/day) or placebo after titrating basal insulin doses to achieve a fasting blood glucose <140 mg/dL. After 20 weeks, both groups experienced a reduction in A1C of 1.4–1.6%, but the difference between the groups was not statistically significant. The mean daily insulin dose was lower in the pioglitazone group (mean difference 12 units, P <0.001), but more patients in the pioglitazone group experienced hypoglycemia (46 vs. 31%, P <0.005). Weight gain was greater in the pioglitazone group than the placebo group (4.4 vs. 2.2 kg, statistical comparison not reported). The magnitude of weight gain appears to be comparable to what patients might experience when switching to U-500 insulin. However, the lack of improvement in glycemic control, coupled with potential serious adverse effects (e.g., heart failure and fractures), limit the usefulness of this class of agents in patients with severe insulin resistance (6,22).

Other Therapies

Several other oral antidiabetic therapies are available, but there is a lack of evidence and experience using these agents in patients with severe insulin resistance. Given the very high insulin requirements of patients with severe insulin resistance, sulfonylureas or meglitinides are not likely to have any clinical utility. α-Glucosidase inhibitors (AGIs) reduce prandial hyperglycemia by retarding hydrolysis of complex carbohydrates. The AGI acarbose was studied in patients with type 2 diabetes with a mean total daily dose of insulin of 62 units and baseline A1C of 8.7%. After 26 weeks of therapy, patients who received acarbose had a significant reduction in A1C of 0.7%. However, these findings have not been replicated in patients with severe insulin resistance, and dose-dependent GI effects (i.e., flatulence, diarrhea, and abdominal pain) often limit use of these agents (48). Colesevelam is a bile acid sequesterant approved to treat hyperlipidemia and type 2 diabetes. The mechanism for its glucose-lowering effect is unknown (49). It has been shown to produce a modest reduction in A1C of 0.5% in patients treated with ∼75 units of insulin/day in one 16-week study (50). Bromocriptine is a dopamine receptor agonist indicated as adjunct therapy for type 2 diabetes, but its efficacy has not been evaluated in patients taking insulin (51).

Conclusion

Several medications are available to treat patients with type 2 diabetes, but few have been studied in the setting of severe insulin resistance (Table 2). The majority of patients with severe insulin resistance will likely have taken metformin. For patients who are currently taking metformin with insulin therapy, the metformin should be continued based on its track record of safety and efficacy, low cost, and potential to reduce the long-term complications related to diabetes (52). In the absence of a true contraindication, metformin should be added to high-dose U-100 insulin therapy if patients are able to tolerate it. However, switching patients to U-500 regular insulin or adding a GLP-1 receptor agonist will produce greater reductions in blood glucose and be more likely to achieve glycemic goals. U-500 regular insulin has the most data and greatest clinical experience to support its use in patients with severe insulin resistance, but weight gain is a problem that can escalate insulin resistance and dose requirements over time. GLP-1 receptor agonists, although not as potent as U-500 regular insulin in terms of A1C reduction, are an attractive alternative for obese patients with severe insulin resistance (53). SGLT2 inhibitors and pramlintide have a favorable impact on weight and can be considered. Other treatment options offer limited benefits but may be useful in specific patient circumstances. There is a paucity of evidence regarding the optimal treatment of patients with severe insulin resistance, and many questions remain unanswered.

TABLE 2.

Pharmacological Treatment Options in the Setting of Severe Insulin Resistance

Medication Class A1C Lowering* Hypoglycemia Risk Weight Effect Ease of Use Tolerability Issues Relative Cost† 
Treatment options that have been evaluated in patients with severe insulin resistance 
U-500 regular insulin ↓↓↓ ↑ ↑↑ Subcutaneous; two to four times daily   
GLP-1 receptor agonists ↓↓ ←→ ↓↓ Subcutaneous; once daily or once weekly Nausea, vomiting $$$ 
Metformin ↓ ←→ ←→,↓ One to four tablets once or twice daily Diarrhea, loose stools $ 
Treatment options that have not been evaluated in patients with severe insulin resistance 
SGLT-2 inhibitors ↓ ←→ ↓ Oral; once daily Urogenital infections $$$ 
DPP-4 inhibitors ↓ ←→ ←→ Oral; once daily Well tolerated $$$ 
TZDs ↓ ←→ ↑↑ Oral; once daily Lower extremity edema, new-onset heart failure $$$ 
Pramlintide ↓ ↑, ←→ ↓ Subcutaneous; two to three times daily Nausea, vomiting  
Sulfonylureas ↓ ↑ ↑ Oral; once or twice daily  $ 
Meglitinides ↓ ↑ ↑, ←→ Oral; two or three times daily  $$ 
α-Glucosidase inhibitors ↓ ←→ ←→ Oral; three times daily Flatulence, GI distress $ 
Colesevelam ↓ ←→ ←→ Oral; one packet or six tablets once daily Constipation $$$ 
Bromocriptine ↓ ←→ ←→ Oral; four to six tablets once daily Nausea, vomiting, somnolence, rhinitis, dizziness $$$ 

Additional A1C lowering in previously treated patients; ↓ = 0.5–1%, ↓↓ = 1–1.5%, ↓↓↓ =1.5–2%.

Relative cost per 30-day supply; $ = <$100,

Are Post-Meal Insulin Surges Beneficial?

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Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.

“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”

The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.

Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.

As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Retnakaran told Medscape Medical News. 

However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.

Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.

To investigate the issue in a longitudinal context, Dr Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.

The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.

Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).

However, those trends were also associated with progressively improved beta cell function (P < .001).

After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).

The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.

Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).

“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Retnakaran told Medscape Medical News. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”

While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.

“This evidence should help push back concern around the postprandial insulin spike,” Retnakaran said.

Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told Medscape Medical News.

However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.

“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”

A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.

Nevertheless, “I think this is an interesting and important study,” Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”

Are Post-Meal Insulin Surges Beneficial?

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0


Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.

“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”

The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.

Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.

As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Retnakaran told Medscape Medical News. 

However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.

Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.

To investigate the issue in a longitudinal context, Dr Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.

The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.

Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).

However, those trends were also associated with progressively improved beta cell function (P < .001).

After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).

The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.

Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).

“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Retnakaran told Medscape Medical News. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”

While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.

“This evidence should help push back concern around the postprandial insulin spike,” Retnakaran said.

Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told Medscape Medical News.

However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.

“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”

A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.

Nevertheless, “I think this is an interesting and important study,” Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”

6 Benefits of Insulin Resistance Diet, Beyond Preventing Diabetes: Current Research

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(siam.pukkato/Shutterstock)

Insulin resistance is a condition that occurs when the body’s cells become less responsive to the hormone insulin, which plays a critical role in regulating blood sugar levels.

Over time, this can lead to the development of serious health conditions such as Type 2 diabetes, heart disease, and obesity. Fortunately, following an insulin resistance diet has been shown to have numerous health benefits, even for people who don’t have diabetes, or aren’t overweight or obese.

Insulin Resistance Can Affect Anyone

Insulin resistance is a condition that can affect anyone—temporarily or chronically. Left untreated, chronic insulin resistance could lead to prediabetes and eventually Type 2 diabetes.

Prediabetes is when your blood sugar levels are higher than normal, but not yet high enough to be diagnosed as diabetes. It typically occurs in those who are already living with some degree of insulin resistance.

It’s important to keep track of your blood sugar levels to know when you’re becoming insulin resistant. Your doctor can check this using a special test that finds out your average blood sugar levels over three months. It’s called the baseline A1C test.

It’s recommended that adults who are over age 45, overweight, and have risk factors for prediabetes or Type 2 diabetes be tested.

The insulin resistance diet is a nutritional approach that aims to regulate blood sugar levels by reducing the intake of foods that are high in sugar, refined carbohydrates, and unhealthy fats. Instead, it emphasizes the consumption of foods that are low in carbohydrates, high in fiber, and rich in healthy fats and proteins.

The goal of this diet is to help the body use insulin more effectively.

The Diabetes Plate Method

“A diet rich in minimally processed whole foods containing fiber, lean protein, and healthy fats [is] best for insulin resistance and diabetes,” Emily Feivor, a registered dietitian at Long Island Jewish Forest Hills, part of Northwell Health in New York, told The Epoch Times.

The diabetes plate method is an easy way to eat meals that help manage your blood sugar levels.

The American Diabetes Association recommends starting with a dinner plate that’s about nine inches across. You’ll then fill half your plate with non-starchy vegetables like broccoli, asparagus, or Brussels sprouts.

Next, fill one-quarter of your plate with lean protein foods. These include chicken, salmon, and lean beef. The last quarter of the plate will consist of healthy carbohydrates that can include whole grains, fruit, and beans. Finally, any beverage you include with your meal should be zero-calorie, or simply water.

Feivor recommends that people who want to control their blood sugar avoid refined and processed carbohydrates.

For example, eat steel-cut oats instead of sweetened instant oatmeal. Also, avoid processed meat/high-fat red meats because they’re high in saturated and trans fats, and avoid drinking too many alcoholic or sugary beverages.

Benefits of Insulin Resistance Diet Beyond Preventing Diabetes

Besides reducing the risks of diabetes or its complications, eating an insulin resistance diet offers at least six important health benefits.

1. Improved Heart Health

A primary benefit of following the insulin resistance diet is improved heart health.

High blood sugar can damage blood vessels, increasing the risk of heart disease. An insulin resistance diet helps reduce this risk by regulating blood sugar levels.

Research published in the British Medical Journal found that eating a diet high in sugar for just a few weeks led to about one-third of men experiencing many changes typically seen in heart and vascular disease. However, a diet low in added sugars and refined carbohydrates was found to reverse this.

2. Weight Loss

Being overweight or obese is linked to insulin resistance. By reducing the intake of carbohydrates and sugar, an insulin resistance diet can help individuals lose weight and reduce their risk of obesity.

“Weight loss and physical activity can play an important role in improving insulin resistance,” said Feivor.

3. Improved Energy Levels

Individuals who follow an insulin resistance diet often report improved energy levels. This could be because the diet encourages the consumption of nutrient-dense foods that provide sustained energy throughout the day.

A randomized controlled feeding trial published in the journal Appetite found eating a low glycemic index diet (very similar to an insulin resistance diet) was associated with “significantly” higher scores for vigor/activity and significant reductions in fatigue compared to a high glycemic index (high sugar) diet.

Additionally, regulating blood sugar levels can prevent the highs and lows associated with a diet high in sugar and refined carbohydrates.

4. Reduced Inflammation

Chronic inflammation is a risk factor for many health conditions, including heart disease, cancer, and even dementia.

High blood sugar levels can contribute to inflammation in the body. By regulating blood sugar levels, an insulin resistance diet may reduce inflammation and improve overall health.

5. Improved Brain Health

The brain relies on glucose for energy, but high levels of glucose can be damaging to brain cells. By regulating blood sugar levels, an insulin resistance diet could protect the brain and improve cognitive function.

A study published in the journal Advances in Nutrition found that a low glycemic index diet improved cognitive function. This might be due to lower blood sugar concentration after a low glycemic index meal that caused brain changes that made participants feel less stressed or nervous before memory tests, improving their performance.

6. Reduced Risk of Cancer

Following an insulin resistance diet might also reduce cancer risk. There is strong evidence that high levels of insulin contribute to the growth of cancer cells.

By reducing our intake of carbohydrates and regulating blood sugar levels, an insulin resistance diet can reduce the amount of insulin in the body to potentially reduce the risk of cancer. Research shows that a low-carbohydrate, high-protein diet (also good for insulin resistance) not only reduces cancer risk, but can also slow tumor growth if cancer is already present.

This Soothing Drink Reduces Insulin Resistance, Lowers Blood Pressure & Fights Cancer

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Close-up of woman hand holdin the cup of tea with stamp against the sun and lake in the nature

You’re going to want to put on the kettle after learning this good news. Just one cup of green tea a day can not only help you fight cancer, but can reduce insulin resistance, lower blood pressure, and reduce belly fat.

Tea leaves are one of the richest sources of polyphenols known to man, and they are a natural source of anti-oxidants that work hard to mop up harmful free radicals in your body. Certain compounds in green tea known as Epigallocatechin gallate (EGCG) are particularly powerful cancer inhibitors. Why? EGCG works at the cellular level to intervene against various cancers and suppress tumor growth. Green tea’s EGCG benefits are part of the Rath Protocol, which I wrote about it in my book, I Used to Have Cancer.

Of the more than 10 catechin compounds found in tea, EGCG is the most abundant and it accounts for more than 40% of the catechins in green tea leaves. EGCG has also been proven to have the most suppressive effect on cancer. Studies like the one published August 2016 in Nutrients entitled “Suppressive Effects of Tea Catechins on Breast Cancer,” back it up.

Teas are typically classified into three categories based upon the way they are processed:

Unfermented green tea
Semi-fermented Oolong tea
Fully-fermented black tea

According to the aforementioned study, this classification is based on the degree of fermentation, during which catechins are oxidized.
Green Tea and Insulin Resistance

Dr. Eric Berg highlights the connection between cortisol (the body’s main stress hormone) and insulin resistance in this short video. He explains that when you’re exposed to cortisol over a long period of time, it’s like being exposed to a high level of insulin over a long period of time. Your body starts developing what’s commonly called insulin resistance. The body’s adrenals are forced to pump more and more cortisol. Unfortunately, that only compounds the problem.

Cortisol is an important hormone and enables us to move quickly to the “fight or flight” reaction needed in emergency situations. However, when we’re expressing excess stress, whether real or imagined, too much cortisol in the body can result in increased depression, anxiety, increased blood pressure, and increased risk of cancer. An increase in belly fat can be an early warning sign that your cortisol levels are too high, for too long.

It’s EGCG, the compound found in green tea, that works to inhibit the enzyme that converts the inactive to the active form of cortisol to the active form of cortisol.

By consistently drinking this inexpensive green tea every day, studies show that you can significantly lower your cortisol levels, decrease your risk of cancer, reduce your levels of depression, lose the belly fat and improve your overall health.
A Word of Caution

It’s important to select organically grown green tea. Nutritionists such as Ann Louise Gittleman, PhD, CNS, have warned about the importance of finding a quality tea, one that is not contaminated. Gittleman explains that teas from China and India tend to be the most contaminated, as China is the world’s top pesticide user. Japanese teas tend to be better, but since the Fukushima disaster, we must keep radioactive contamination in mind. In general, organic teas will have fewer pesticides, but may be high in fluoride.

Make green tea Cups of green tea on table on wooden background

One of her top picks includes Pique Tea that delivers up to 12x the antioxidant polyphenols of regular tea. No wonder it’s more potent and powerful than any other tea on the market! Pique Tea is made from the highest quality tea leaves and natural ingredients that are organic, sugar-free, and free of additives. Another reassurance: the company triple screens for pesticides, mycotoxins, and heavy metals.

Why Your Depression May Really Be Insulin Resistance.

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Influence of insulin resistance illustrates heightened CVD risk in ‘pre-prediabetes’

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 Insulin resistance is a more important cardiometabolic risk factor than glucose tolerance, increasing cardiovascular risk even before hyperglycemia increases risk for diabetes, according to a speaker at the third annual Heart in Diabetes conference.

Ralph A. DeFronzo

“I’m not really a believer that hyperglycemia is a major risk factor in developing cardiovascular disease, and the problem starts long before you develop diabetes,” Ralph A. DeFronzo, MD, director of the diabetes research unit at the University of Texas Health Science Center at San Antonio, said during the presentation. “You’re going to see a new word that’s going to be introduced and that’s ‘pre-prediabetes,’ because the disease actually starts long before you become prediabetic, and the implication for this, of course, is that glucose is really not the big bad actor in the development of cardiovascular disease.”

Glucose level effect on CV risk

DeFronzo and colleagues conducted a meta-analysis in which they examined findings from 19 studies to determine whether prevalence and risk for CV complications, such as acute myocardial infraction, as well as mortality differed significantly between different ranges of glucose tolerance. Each study excluded participants with diabetes or prediabetes or previous MI at baseline.

The researchers found that among 41,509 patients who developed acute MI during the studies, 51.5% had normal glucose tolerance whereas 28.8% had developed prediabetes and 19.7% had developed diabetes. DeFronzo noted that a coin flip essentially determined whether participants with diabetes or prediabetes or those with normal glucose tolerance would experience an MI.

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Insulin resistance is a more important cardiometabolic risk factor than glucose tolerance, increasing cardiovascular risk even before hyperglycemia increases risk for diabetes.

Adobe Stock

The meta-analysis further revealed that participants with prediabetes had a 43% higher major adverse cardiovascular event incidence ratio than those with normal glucose tolerance whereas those with diabetes had a 50% increase in the ratio. In addition, compared with those with normal glucose tolerance, those with prediabetes had a 44% higher incidence rate ratio for annual mortality, and the measure was 71% higher for those with diabetes.

However, the differences between the groups with prediabetes and diabetes for both MACE and mortality did not reach significance, suggesting that the progression from HbA1c levels associated with prediabetes to those with diabetes does not alter CV risk to a significant degree, according to DeFronzo.

Insulin resistance predicts CVD

DeFronzo said that the underlying elements of metabolic syndrome, or what he calls “insulin resistance syndrome,” is where the real problem resides. These include obesity, hypertension, dyslipidemia, inflammation and hyperinsulinemia, which DeFronzo said have all showed similar insulin resistance rates compared with diabetes in insulin clamp studies.

“That’s why if you have diabetes and you gain weight, that’s a major problem; because now you’re superimposing the insulin resistance of obesity on the insulin resistance of diabetes,” DeFronzo said during the presentation. “These are all very different diseases, but they all have the same biochemical defect. … The insulin resistance is there long before you develop diabetes.”

Even when looking at glucose measures, DeFronzo warned against lumping measures of impaired fasting glucose and impaired glucose tolerance together when assessing risk. Although there is an association between heightened CVD risk and IGT as measured by 2-hour oral glucose tolerance tests, the same does not hold for IFG.

“You cannot have the same pathophysiology with people with IGT,” DeFronzo said during the presentation. “When we talk about IGT, you really have to distinguish between IGT and IFG.”

DeFronzo and colleagues performed an additional meta-analysis of 17 studies that assessed how well CVD could be predicted by insulin resistance. One study revealed that those with higher measures of insulin resistance according to HOMA-IR were at greater risk for CVD over 8 years of follow-up, and another found that the relative risk for coronary heart disease reached 73% for those with normal glucose tolerance and metabolic syndrome vs. those without metabolic syndrome.

To combat insulin resistance and its apparent ability to raise CVD risk, DeFronzo outlined details from the Insulin Resistance after Stroke study in which researchers recruited 3,876 participants without diabetes but with insulin resistance who had experienced a stroke. Participants were randomly assigned to either pioglitazone or placebo during 5 years of follow-up. Pioglitazone reduced the incidence of recurrent stroke or MI by 24% (HR = 0.76; 95% CI, 0.62-0.93) and also had positive effects on obesity, hypertension and dyslipidemia, according to DeFronzo.

“I would argue that the best drug that we have for the treatment of cardiovascular disease is pioglitazone,” DeFronzo said. “The problem is there’s a perception with pioglitazone and that’s the problem. It’s not that the drug doesn’t work.”

DeFronzo further described the molecular mechanisms that lead to the blocking of nitric oxide and activation of atherogenesis as well as genetically inherited insulin resistance, which means that developing CVD can be just a matter of time for some patients.

“The whole story of hyperglycemia in diabetes has really very little to do with cardiovascular disease. The problem starts long before you are hyperglycemic,” DeFronzo said. “From the diabetic standpoint, we’ve got to control the glucose. We don’t want people going blind or on dialysis. However, that has very, very little to do with protection against cardiovascular disease. From the standpoint of cardiovascular disease, what we really need to do is to correct the underlying components of the insulin resistance syndrome.” – by Phil Neuffer

Reference:

DeFronzo RA, et al. Prediabetes: The Prelude to Macrovascular Complications. Presented at: Heart in Diabetes CME Conference; July 12-14, 2019; Philadelphia.

Hanley AJG, et al. Diabetes Care. 2002;doi:10.2337/diacare.25.7.1177.

Insomaa B, et al. Diabetes Care. 2001;doi: 10.2337/diacare.24.4.683.

Kernan WN, et al. N Engl J Med. 2016;doi: 10.1056/NEJMoa1506930.

Vitamin D supplementation does not affect insulin resistance in children

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Healthy black and white children randomly assigned varying doses of vitamin D over 12 weeks saw no changes in insulin resistance measurements, study findings show.

Ashley J. Ferira, of the University of Georgia, and colleagues analyzed data from 323 black and white children aged 9 to 13 years (50% boys; 51% black; 21% with overweight; 21% with obesity; 5% meeting prediabetes criteria) participating in the GAPI vitamin D supplementation trial. Researchers randomly assigned one of four doses of vitamin D for 12 weeks (400, 1,000, 2,000 or 4,000 IU daily) or oral placebo. Researchers measured fasting serum 25-hydroxyvitamin D, glucose and insulin at baseline and 6 and 12 weeks; homeostasis model assessment of insulin resistance (HOMA-IR) was used to measure insulin resistance.

Researchers found that baseline serum 25-(OH)D was inversely associated with insulin (r = –0.14; P = .017) and HOMA-IR (r = –0.146; P = .012) after adjustment for race, sex, age, pubertal maturation, fat mass and BMI. However, glucose and insulin levels and insulin resistance increased over 12 weeks (P < .003), despite vitamin D dose-dependent increases in serum 25-(OH)D.

“The significant increase in all three outcomes in this study suggests that this phenomenon was occurring organically in our children over the course of the trial,” the researchers wrote. “We observed that female, black and high-fat children were more insulin resistant than male, white and normal-fat children, respectively. We addressed these possible confounding variables statistically; however, none remained significant in the final models.”

NAFLD Risk Higher for Women With Long or Irregular Menstrual Cycles

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This link wasn’t fully explained by obesity, insulin resistance, researchers say

A black and white close up of a woman holding a tampon between her thumb and index finger.

Abnormal periods may put young women at a higher risk for developing nonalcoholic fatty liver disease (NAFLD), a Korean study suggested.

Among 72,092 premenopausal women under the age of 40, long or irregular menstrual cycles were linked to a 22% higher risk for incident NAFLD after adjusting for age, BMI, insulin resistance, and other factors (HR 1.22, 95% CI 1.14-1.31), reported Seungho Ryu, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul, and colleagues.

In a time-dependent analysis, this relationship only strengthened the more irregular a cycle was, the group noted in the Journal of Clinical Endocrinology and Metabolism.

More specifically, women with irregular cycles lasting over 31 days in between periods saw this increased risk, with 40-day or longer cycles tied to the highest risk:

  • 31- to 39-day cycles: HR 1.27 (95% CI 1.15-1.39)
  • ≥40-day cycles: HR 1.49 (95% CI 1.38-1.60)

“Importantly, our results indicate that menstrual irregularity, which is easier to diagnose and usually presents earlier than PCOS [polycystic ovary syndrome], highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” Ryu’s group wrote.

“This link was not explained by obesity,” Ryu added in a statement. “Previous studies have shown that long or irregular menstrual cycles are associated with type 2 diabetes and cardiovascular disease, but our study is the first to find a link between long or irregular menstrual cycles and NAFLD.”

“Young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD as well as other cardiometabolic diseases,” he suggested.

In a subgroup analysis of women with a homeostatic model assessment of insulin resistance (HOMA-IR) less than 2.5 — indicating less insulin resistance — these associations were weakened but were still significantly high: women with 31- to 39-day and ≥40-day irregular menstrual cycles saw an 18% and 27% higher risk for developing NAFLD, respectively.

“This suggests that insulin resistance, which has been posited to contribute to the association between PCOS and NAFLD, does not fully explain the association between long or irregular menstrual cycles and NAFLD demonstrated in our study,” the researchers pointed out.

The group explained that while the mechanisms underlying the association between long or irregular menstrual cycles and NAFLD aren’t fully clear just yet, some possible explanations could be estrogen exposure, androgen excess, and hypogonadotropic hypogonadism.

The study’s final cohort included Korean women under the age of 40 who underwent annual exams at a health center in Seoul and Suwon, South Korea. Exclusion criteria included a history of liver disease, hepatitis B or C, higher alcohol consumption, and abnormal thyroid functioning.

NAFLD diagnosis was based on hepatic steatosis identified on abdominal ultrasonography performed by radiologists. At baseline, 7.1% of women had prevalent NAFLD and 27.7% had long or irregular menstrual cycles. During a median 4.4-year follow-up period, 8.9% of women developed incident NAFLD.

Ryu’s group noted that diagnosing NAFLD via ultrasonography instead of histological diagnosis — the “gold standard” — was a limitation to the study, but explained that ultrasonography was a more appropriate option for routine health screening examinations.

Sleep-disordered breathing early in pregnancy linked to insulin resistance

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Sleep disordered breathing is associated with an increase in insulin resistance but not insulin secretion during early pregnancy among women with overweight and obesity, according to a study published in Sleep.

“We decided to conduct this study to better understand the association between maternal sleep disordered breathing (SDB) and glucose metabolism in early pregnancy,” author Laura Sanapo, MD, MSHS, RDMS, a research scientist with the Miriam Hospital, Women’s Medicine Collaborative in Providence, Rhode Island, told Healio.

Women often experience snoring and obstructive sleep apnea (OSA) during pregnancy, Sanapo said. SDB also is underdiagnosed, although it affects up to 70% of high-risk pregnancies, she continued, especially those complicated by maternal obesity, and it is more common than other obstetric complications such as diabetes and hypertension.

Previous research has demonstrated that women with SDB during pregnancy have a higher risk for developing diabetes in late gestation than women without SDB after controlling for obesity and other confounding factors, according to Sanapo.

Yet whether women with SDB at the beginning of gestation start pregnancy with glucose abnormalities that precede the onset of diabetes such as reduced insulin sensitivity was unknown, Sanapo added.

What the study showed

The cross-sectional study was based on the baseline characteristics of 192 women with singleton pregnancies and risk factors for OSA such as a BMI equal to or greater than 27 kg/m2 and snoring three or more days per week.

The researchers conducted home sleep apnea testing (HSAT) at 11 weeks of gestation and homeostatic model assessments (HOMA) at 15 weeks.

HSAT found 61 participants (32%) with OSA based on respiratory-event index (REI) values of five events or more per hour. These participants were older, had a higher BMI and were more likely to be multipara than those not diagnosed with OSA.

Virtually all the respiratory events were obstructive, and both groups saw minimal sleep hypoxemia. The median REI was categorized as mild (fewer than 15 events per hour), though 10 women had REI values of more than 15 events per hour.

HOMA, designed to yield an estimate of insulin resistance, sensitivity and B cell function (HOMA %B), measured fasting glucose and c-peptide. Venipuncture following an 8-hour fast provided morning blood.

Participants who were diagnosed with OSA exhibited higher glucose and c-peptide values and had a higher degree of insulin resistance (HOMA-IR) than the participants who were not diagnosed with OSA, the researchers said.

For each 10-unit increase in REI, there was a 0.3-unit increase in HOMA-IR and a 4-unit increase in fasting glucose levels. However, there was no significant association between REI and HOMA %B.

The researchers also found an association between HOMA-IR and oxygen desaturation index (ODI), but they did not find an association between ODI and HOMA %B.

Further, 20 participants (32.8%) in the OSA group and 22 (16.8%) in the non-OSA group had fasting glucose levels of 95 mg/dL or higher. REI and ODI both were associated with fasting glucose levels after adjusting for the same covariates (B = .22; P = .012 and B = .27; P = .003, respectively).

Laura Sanapo

“Among a group of women without pregestational diabetes, those who are diagnosed with SDB at the beginning of pregnancy have lower sensitivity to insulin and higher fasting glucose levels compared to pregnant women without SDB,” Sanapo said.

The researchers controlled for several factors that may contribute to abnormal glucose markers in pregnancy such as maternal BMI, age, race, ethnicity and number of previous pregnancies.

Why the findings are important

Sanapo said these results were important for four reasons.

First, a reduced sensitivity to insulin usually precedes the development of diabetes. Second, the study showed this association between SDB and reduced insulin sensitivity very early in pregnancy, approximately 10 weeks before typical screenings for gestational diabetes in the general pregnant population.

Third, Sanapo noted that the normal range of insulin resistance in pregnancy is very narrow, so even mild changes related to maternal SDB can lead to abnormal values. Finally, SDB is a modifiable risk factor that can be treated by non-pharmacological interventions that are safe in pregnancy.

“Therefore, women with overweight and obesity may benefit from SDB screening before conception or early pregnancy to improve glucose metabolic outcome and decrease the risk of developing diabetes in pregnancy,” Sanapo said.

These women then may benefit from tailored interventions to improve pregnancy outcomes such as early gestational diabetes screenings and SDB therapy, though weight loss or exercise programs are not usually advised in pregnancy, Sanapo said.

“Hence, the ideal time to actually screen and intervene would be in reproductive-age women considering pregnancy,” she said.

The researchers now aim to better understand the mechanistic processes that connect these disorders to identify therapeutic targets. They also seek to establish whether screenings should be universal or for select groups of high-risk pregnancies, or if screenings should occur before conception.

Further, the researchers aim to evaluate whether SDB treatment can prevent the development of gestational diabetes or other adverse perinatal outcomes.

“SDB represents a common morbidity in high-risk pregnancies and is associated with many disorders that are directly linked or considered an important contributor to maternal mortality,” Sanapo said. “Research in this field is needed and may greatly impact maternal health.”

Reference:

For more information:

Laura Sanapo, MD, MSHS, RDMS, can be reached at laura_sanapo@brown.edu.

PERSPECTIVE

Uma M. Reddy, MD, MPH

Previous studies have shown that SDB is associated with gestational diabetes, which is typically diagnosed at 24 to 28 weeks of pregnancy and affects 7% of all pregnancies. It is not clear if both conditions coexist in the same patients because they are at increased risk for both SDB and gestational diabetes mellitus.

The results of this study are significant and novel in that SDB early in pregnancy was associated with increased insulin resistance early in pregnancy, which may be the pathway for the development of gestational diabetes later in pregnancy. Therefore, SDB is a potentially modifiable risk factor that, if treated early in pregnancy, may decrease the risk of gestational diabetes.

Prior to changing care, further research is needed to understand if screening pregnant people for SDB early in pregnancy and treating with CPAP decreases the rate of development of gestational diabetes. Also, it is important to study if pregnant people with normal or low BMI diagnosed with SDB are at increased risk for gestational diabetes, as only a high-risk population was studied.Uma M. Reddy, MD, MPHProfessor of obstetrics and gynecology, vice chair of research, department of obstetrics and gynecology, Columbia University Irving Medical Center