Pancreas

New hormone stimulates pancreatic β-cell proliferation.

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Diabetes affects more than 360 million people worldwide and its prevalence is increasing, with 552 million diabetics predicted worldwide by 2030. Scientists recently discovered a hormone that could improve future diabetes management by stimulating replenishment of insulin-producing β cells in the pancreas.

The hormone, which has been named betatrophin, was discovered in studies of a mouse model of severe insulin resistance in which chemical blockade of insulin receptors induced pancreatic β-cell proliferation. Betatrophin was identified in murine liver and fat, and its stimulatory effect on cellular replication was limited to β cells. Its expression was also reported in human liver tissue.

Betatrophin treatment of mice increased proliferation of pancreatic β-cells by an average of 17-fold within a few days, causing an expansion of β-cell mass and increased insulin concentrations in the pancreas.

Betatrophin’s discovery “is a very exciting new development, and is only the beginning of the story”, says C Ronald Kahn (Joslin Diabetes Center, Boston, MA, USA). He adds that unanswered questions include whether “action on islets is direct or indirect. We don’t know how betatrophin works; is it only one growth factor or one of many? There is a lot of future work to be done”.

Senior author Douglas Melton (Harvard University, Cambridge, MA, USA) said: “It’s not often that one finds a new hormone, so it opens up all kinds of possibilities for new treatments”.

The most immediate application for betatrophin is for the “millions of prediabetics who are on their way to getting type 2 diabetes. If these individuals still have β cells, this hormone could give them more β cells and alleviate the need for insulin injections”, Melton continued. Betatrophin may also prove beneficial in type 1 diabetes, which is initiated by an autoimmune process. “If the disease is just starting, one could give an immunosuppressant and this hormone to forestall the onset of type 1 diabetes.”

Melton cautions that results from human studies should not be expected quickly. “We are currently working with our collaborators Evotec and Janssen to make the human betatrophin protein. This will take more than a year.” Results from studies in humans might be available “2—3 years from now, if all goes well”.

Source: Lancet

Intensive insulin for type 2 diabetes: the risk of causing harm.

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The ACCORD study showed that aggressive intensification of glycaemic control in patients with type 2 diabetes can increase mortality (hazard ratio [HR] 1·22, 95% CI 1·01—1·46), including death from cardiovascular causes (1·35, 1·04—1·76).1 The reason for this unexpected finding is unknown. Of note was the high percentage of intensively treated patients receiving insulin therapy (77%) or thiazolidinedione therapy (with or without insulin) (92%), and their greater weight gain (3·5 kg vs 0·4 kg).1 Results of post-hoc analyses did not support the hypothesis that increased hypoglycaemia in patients who were intensively treated caused the excess deaths.2 The analyses showed, however, that a higher baseline HbA1c and a failure to improve average HbA1c throughout the study were linked to the increased mortality.3

In view of the findings of the ACCORD study, we propose that development of insulin resistance in crucial tissues such as the heart is a protective response to persistently raised glucose concentrations. We postulate that overriding insulin resistance in attempts to lower glucose with exogenous insulin—particularly in overweight and obese patients with the most refractory hyperglycaemia—could undo this protection and cause harm.

For decades the dogma has been that insulin resistance is mostly pathological. However, regulation of insulin sensitivity is an integral component of normal metabolic physiology, including, at times, the induction of insulin resistance. For example, in response to even short-term overfeeding, skeletal and cardiac muscle develops insulin resistance,4 which promotes diversion of excess nutrients to adipose tissue for safe storage. We, and others, have proposed that this induction of insulin resistance protects important tissues from nutrient-induced dysfunction.5

The myocardium, with its high energy needs, adapts to the predominant nutrient source, which is free fatty acids (FFA) during fasting and glucose in the fed state. In poorly controlled type 2 diabetes, the reciprocal relationship between FFA and glucose is lost and both are simultaneously raised. This places the myocardium at increased risk of nutrient overload and myocardial glucolipotoxicity.5, 6 We propose, however, that insulin resistance is a safeguard against glucolipotoxicity because it limits myocardial glucose uptake. Treatment of patients with the most refractory hyperglycaemic and hyperlipidaemic type 2 diabetes with large amounts of exogenous insulin could override this block against glucose entry, providing all the ingredients for glucolipotoxicity,6 a process that we have termed insulin-mediated metabolic stress. In the heart, this process would cause a metabolic cardiomyopathy. Jagasia and colleagues7 provided evidence that insulin resistance is easier to override in the myocardium than in skeletal muscle in patients with type 2 diabetes. Exogenous insulin tripled myocardial glucose uptake without compensatory reduction in FFA uptake,7 which is consistent with the capacity of exogenous insulin to drive excess nutrients into the heart. If the same mechanisms of insulin-mediated metabolic stress can function in skeletal muscle, inappropriate high-dose insulin use in patients with type 2 diabetes could also induce a metabolic myopathy that impairs the patient’s ability to exercise.

If our proposition is correct—that intensive treatment of type 2 diabetes with insulin is potentially harmful to overweight and obese patients with the most refractory hyperglycaemia—there should be support for it in clinical trials. In the major trials of intensive versus conventional glucose control, and insulin versus other glucose-lowering therapies, whenever high use of insulin was associated with weight gain of greater than 1 kg per year (ACCORD,1 VADT,8 DIGAMI-29), cardiovascular or all-cause mortality, or both, were increased, reaching statistical significance only in the higher powered ACCORD study. UKPDS, ADVANCE, and ORIGIN did not show increased cardiovascular disease or mortality in the intensive control or insulin therapy groups. However, the patient characteristics and the aggressiveness of insulin use differed greatly from those in ACCORD. Careful analysis showed that UKPDS, ADVANCE, and ORIGIN were not studies of intensive insulin use in obese patients with the most refractory hyperglycaemia. While results of population-based studies have shown increased risk of mortality in patients with type 2 diabetes treated with insulin, they are observational and should be interpreted with caution.10

Patients with type 2 diabetes should be considered individually, because their relative need for insulin resistance as a protective mechanism and the potential for long-term benefit from tight blood glucose control will differ. For example, an overweight individual with type 2 diabetes unable to exercise because of comorbidities will have much more difficulty achieving lifestyle change to overcome a state of positive energy balance (figure). In these patients, insulin resistance might be necessary to protect crucial tissues such as the heart and skeletal muscle against excess nutrient entry. An aggressive approach to lower blood glucose with insulin will override this protection, increasing the risk of insulin-mediated metabolic stress in these key tissues (figure). Furthermore, these patients are least likely to be able to adequately achieve lower HbA1c concentrations—the group that was at highest risk in ACCORD.3 Careful amelioration of very high blood glucose, however, will be necessary in these individuals. At the other end of the spectrum, a patient with type 2 diabetes who can avoid positive energy balance by lifestyle change will be at much lower risk of the harmful consequences of an aggressive approach to glucose lowering with insulin.

The safety of insulin sensitisers is probably associated with the mechanism by which they work. Those that enhance nutrient detoxification should be beneficial. Such agents are very different from insulin in that they reduce and do not override insulin resistance. Metformin and thiazolidinedione drugs both have mechanisms of action that include nutrient detoxification.5 The development of new insulin sensitisers that do not have a nutrient detoxification mechanism might not be advisable.

Further studies of the effect of insulin therapy on myocardial and skeletal muscle nutrient uptake, storage, and function in obese patients with type 2 diabetes are necessary to further explore the concept of insulin-mediated metabolic stress. Ultimately, carefully designed randomised clinical trials with long-term outcome data will be necessary to assess the safety of insulin therapy, and how best to use it, in obese patients with type 2 diabetes who do not achieve acceptable glycaemic control by other therapies. The results of the ACCORD study suggest that the combination of insulin with thiazolidinedione agents should be used with considerable caution.1 The use of insulin in combination with newer agents that avert positive energy balance, such as the glucagon-like peptide 1 mimetics, warrants particular attention in this challenging group of patients.

CJN has received speaking fees from AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Sharp and Dhome, Novartis, and Novo Nordisk; and has been a member of an advisory board for Sanofi Aventis. NBR and MP declare that they have no conflicts of interest.

References

1 Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 2545-2559. CrossRef | PubMed

2 Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340: b4909. CrossRef | PubMed

3 Riddle MC, Ambrosius WT, Brillon DJ, et al. Epidemiologic relationships between A1C and all-cause mortality during a median 3·4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010; 33: 983-990. CrossRef | PubMed

4 Kraegen EW, Saha AK, Preston E, et al. Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am J Physiol Endocrinol Metab 2006;290: E471-E479. CrossRef | PubMed

5 Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management.Lancet 2011; 378: 169-181. Summary | Full Text | PDF(856KB) | CrossRef | PubMed

6 Taegtmeyer H, Stanley WC. Too much or not enough of a good thing? Cardiac glucolipotoxicity versus lipoprotection. J Mol Cell Cardiol 2010; 50: 2-5. CrossRef | PubMed

7 Jagasia D, Whiting JM, Concato J, Pfau S, McNulty PH. Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation 2001; 103: 1734-1739. CrossRef | PubMed

8 Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-139. CrossRef | PubMed

9 Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia 2011; 54: 1308-1317. CrossRef |PubMed

10 Currie CJ, Poole CD, Evans M, Peters JR, Morgan CL. Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in Type 2 Diabetes. J Clin Endocrinol Metab 2013; 98: 668-677. CrossRef | PubMed

Source: Lancet

Intensive insulin for type 2 diabetes: the risk of causing harm.

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The ACCORD study showed that aggressive intensification of glycaemic control in patients with type 2 diabetes can increase mortality (hazard ratio [HR] 1·22, 95% CI 1·01—1·46), including death from cardiovascular causes (1·35, 1·04—1·76).1 The reason for this unexpected finding is unknown. Of note was the high percentage of intensively treated patients receiving insulin therapy (77%) or thiazolidinedione therapy (with or without insulin) (92%), and their greater weight gain (3·5 kg vs0·4 kg).1 Results of post-hoc analyses did not support the hypothesis that increased hypoglycaemia in patients who were intensively treated caused the excess deaths.2 The analyses showed, however, that a higher baseline HbA1c and a failure to improve average HbA1c throughout the study were linked to the increased mortality.3

In view of the findings of the ACCORD study, we propose that development of insulin resistance in crucial tissues such as the heart is a protective response to persistently raised glucose concentrations. We postulate that overriding insulin resistance in attempts to lower glucose with exogenous insulin—particularly in overweight and obese patients with the most refractory hyperglycaemia—could undo this protection and cause harm.

For decades the dogma has been that insulin resistance is mostly pathological. However, regulation of insulin sensitivity is an integral component of normal metabolic physiology, including, at times, the induction of insulin resistance. For example, in response to even short-term overfeeding, skeletal and cardiac muscle develops insulin resistance,4 which promotes diversion of excess nutrients to adipose tissue for safe storage. We, and others, have proposed that this induction of insulin resistance protects important tissues from nutrient-induced dysfunction.5

The myocardium, with its high energy needs, adapts to the predominant nutrient source, which is free fatty acids (FFA) during fasting and glucose in the fed state. In poorly controlled type 2 diabetes, the reciprocal relationship between FFA and glucose is lost and both are simultaneously raised. This places the myocardium at increased risk of nutrient overload and myocardial glucolipotoxicity.5, 6 We propose, however, that insulin resistance is a safeguard against glucolipotoxicity because it limits myocardial glucose uptake. Treatment of patients with the most refractory hyperglycaemic and hyperlipidaemic type 2 diabetes with large amounts of exogenous insulin could override this block against glucose entry, providing all the ingredients for glucolipotoxicity,6 a process that we have termed insulin-mediated metabolic stress. In the heart, this process would cause a metabolic cardiomyopathy. Jagasia and colleagues7 provided evidence that insulin resistance is easier to override in the myocardium than in skeletal muscle in patients with type 2 diabetes. Exogenous insulin tripled myocardial glucose uptake without compensatory reduction in FFA uptake,7 which is consistent with the capacity of exogenous insulin to drive excess nutrients into the heart. If the same mechanisms of insulin-mediated metabolic stress can function in skeletal muscle, inappropriate high-dose insulin use in patients with type 2 diabetes could also induce a metabolic myopathy that impairs the patient’s ability to exercise.

If our proposition is correct—that intensive treatment of type 2 diabetes with insulin is potentially harmful to overweight and obese patients with the most refractory hyperglycaemia—there should be support for it in clinical trials. In the major trials of intensive versus conventional glucose control, and insulin versus other glucose-lowering therapies, whenever high use of insulin was associated with weight gain of greater than 1 kg per year (ACCORD,1 VADT,8 DIGAMI-29), cardiovascular or all-cause mortality, or both, were increased, reaching statistical significance only in the higher powered ACCORD study. UKPDS, ADVANCE, and ORIGIN did not show increased cardiovascular disease or mortality in the intensive control or insulin therapy groups. However, the patient characteristics and the aggressiveness of insulin use differed greatly from those in ACCORD. Careful analysis showed that UKPDS, ADVANCE, and ORIGIN were not studies of intensive insulin use in obese patients with the most refractory hyperglycaemia. While results of population-based studies have shown increased risk of mortality in patients with type 2 diabetes treated with insulin, they are observational and should be interpreted with caution.10

Patients with type 2 diabetes should be considered individually, because their relative need for insulin resistance as a protective mechanism and the potential for long-term benefit from tight blood glucose control will differ. For example, an overweight individual with type 2 diabetes unable to exercise because of comorbidities will have much more difficulty achieving lifestyle change to overcome a state of positive energy balance (figure). In these patients, insulin resistance might be necessary to protect crucial tissues such as the heart and skeletal muscle against excess nutrient entry. An aggressive approach to lower blood glucose with insulin will override this protection, increasing the risk of insulin-mediated metabolic stress in these key tissues (figure). Furthermore, these patients are least likely to be able to adequately achieve lower HbA1cconcentrations—the group that was at highest risk in ACCORD.3 Careful amelioration of very high blood glucose, however, will be necessary in these individuals. At the other end of the spectrum, a patient with type 2 diabetes who can avoid positive energy balance by lifestyle change will be at much lower risk of the harmful consequences of an aggressive approach to glucose lowering with insulin.

The safety of insulin sensitisers is probably associated with the mechanism by which they work. Those that enhance nutrient detoxification should be beneficial. Such agents are very different from insulin in that they reduce and do not override insulin resistance. Metformin and thiazolidinedione drugs both have mechanisms of action that include nutrient detoxification.5 The development of new insulin sensitisers that do not have a nutrient detoxification mechanism might not be advisable.

Further studies of the effect of insulin therapy on myocardial and skeletal muscle nutrient uptake, storage, and function in obese patients with type 2 diabetes are necessary to further explore the concept of insulin-mediated metabolic stress. Ultimately, carefully designed randomised clinical trials with long-term outcome data will be necessary to assess the safety of insulin therapy, and how best to use it, in obese patients with type 2 diabetes who do not achieve acceptable glycaemic control by other therapies. The results of the ACCORD study suggest that the combination of insulin with thiazolidinedione agents should be used with considerable caution.1 The use of insulin in combination with newer agents that avert positive energy balance, such as the glucagon-like peptide 1 mimetics, warrants particular attention in this challenging group of patients.

Source: Lancet

 

Amputations and socioeconomic position among persons with diabetes mellitus, a population-based register study.

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Abstract

Objective Low socioeconomic position is a known health risk. Our study aims to evaluate the association between socioeconomic position (SEP) and lower limb amputations among persons with diabetes mellitus.

Design Population-based register study.

Setting Finland, nationwide individual-level data.

Participants All persons in Finland with any record of diabetes in the national health and population registers from 1991 to 2007 (FinDM II database).

Methods Three outcome indicators were measured: the incidence of first major amputation, the ratio of first minor/major amputations and the 2-year survival with preserved leg after the first minor amputation. SEP was measured using income fifths. The data were analysed using Poisson and Cox regression as well as age-standardised ratios.

Results The risk ratio of the first major amputation in the lowest SEP group was 2.16 (95% CI 1.95 to 2.38) times higher than the risk in the highest SEP group (p<0.001). The incidence of first major amputation decreased by more than 50% in all SEP groups from 1993 to 2007, but there was a stronger relative decrease in the highest compared with the lowest SEP group (p=0.0053). Likewise, a clear gradient was detected in the ratio of first minor/major amputations: the higher the SEP group, the higher the ratio. After the first minor amputation, the 2-year and 10-year amputation-free survival rates were 55.8% and 9.3% in the lowest and 78.9% and 32.3% in the highest SEP group, respectively.

Conclusions According to all indicators used, lower SEP was associated with worse outcomes in the population with diabetes. Greater attention should be paid to prevention of diabetes complications, adherence to treatment guidelines and access to the established pathways for early expert assessment when diabetic complications arise, with a special attention to patients from lower SEP groups.

 

Source: BMJ

 

 

Hypoglycemia Associated with Death in Critically Ill Patients .

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Moderate-to-severe hypoglycemia is tied to an increased risk for death among patients in the ICU, according to a study in the New England Journal of Medicine.

As part of the NICE-SUGAR trial, roughly 6000 ICU patients were randomized to intensive or conventional glucose control. Nearly half of all patients experienced moderate hypoglycemia (41–70 mg/dL), and 4% had severe hypoglycemia (40 mg/dL or less); the majority of these patients were in the intensive control group. The primary outcome — death within 90 days — was more frequent among those with severe hypoglycemia (35%) or moderate hypoglycemia (29%) than among those with no hypoglycemia (24%).

The authors conclude that “it would seem prudent to ensure that strategies for managing the blood glucose concentration in critically ill patients focus not only on the control of hyperglycemia but also on avoidance of both moderate and severe hypoglycemia.”

Source: NEJM

Antioxidant Therapy Ineffective for Painful Chronic Pancreatitis.

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Pain scores were similar with antioxidants or placebo.

Most patients with chronic pancreatitis suffer from abdominal pain, often the most intransigent and debilitating symptom of the disease. Current treatments have shown limited effectiveness. The use of antioxidants has been the focus of several clinical trials, including a study in India that demonstrated improved pain symptoms with antioxidants (JW Gastroenterol Jul 24 2009).

To further investigate the efficacy of antioxidants, researchers conducted an industry-supported, randomized, placebo-controlled trial at a single center in the U.K. involving 92 patients with at least moderately severe pain occurring at least 7 days during the month prior to randomization. Patients received an antioxidant mixture (77 mg selenium yeast, 226.8 mg d-α-tocopherol, 252.6 mg ascorbic acid, 960 mg l-methionine, and 8.4 mg beta-carotene) 3 times daily or matching placebo for 6 months. Pain was scored on a visual analogue scale during the study visit and through a daily diary. Quality of life was assessed using four different validated instruments.

A total of 70 patients (76%) completed 6 months of therapy. Analyses of both pain scores and quality-of-life scores revealed no differences between groups.

Comment: The current findings are at odds with those of the recent trial in India, which demonstrated a clinically significant benefit of antioxidant therapy. These disparate results might be attributable to the differences in the antioxidant mixtures used or the patient populations studied. Compared with the current study cohort, the Indian cohort was younger, smoked less, and had more idiopathic disease than pancreatitis of alcoholic origin (which characterized the majority of the U.K. cohort). Unfortunately — in the U.S. at least — most patients with chronic pancreatitis fit the profile of the U.K. cohort. Taken together, these trials do not provide sufficient evidence to support the routine use of antioxidants in patients with painful chronic pancreatitis.

Source: Journal Watch Gastroenterology

What’s the Optimal HbA1c Level in Elders?

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In an observational study, glycosylated hemoglobin between 8% and 9% was best.

Experienced clinicians have long recognized that tight glycemic control can be perilous in frail older patients with type 2 diabetes. Now, an observational study addresses that concern. Researchers in San Francisco studied 367 community-dwelling, older patients (mean age, 80) with diabetes who participated in a comprehensive adult day-care program and were unable to live independently. Glycosylated hemoglobin (HbA1c) levels were measured at baseline, and functional decline and death were tracked during 2 years of follow-up (during which, average HbA1c levels didn’t change much).

Analyses were adjusted for potentially confounding variables. Compared with patients in the reference category (HbA1c levels, 7%–8%), patients whose HbA1c levels were between 8% and 9% had a significantly lower incidence of functional decline or death (relative risk, 0.88), and those with HbA1c levels <7% had a nearly significant higher incidence of functional decline or death. Overall, the relation between HbA1c level and functional decline or death was somewhat U-shaped, with the best outcomes among patients in the 8% to 9% range. These basic patterns were noted both among patients who took only oral antidiabetic drugs and those who took insulin.

Comment: This observational study is subject to residual confounding, but it suggests that an HbA1c target in the 8% to 9% range is reasonable for older patients with diabetes who are unable to live independently. The findings support a recent guideline in which less-tight glycemic control is acceptable in older adults with long-standing diabetes (JW Gen Med Jul 24 2012).

Source: Journal Watch General Medicine.

Systemic therapy may boost self-esteem in diabetes.

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In addition to clinical support, self-esteem building is also needed to produce positive outcomes among patients with diabetes, according to a presentation by Janis Roszler, MSFT, RD, CDE.

Roszler, diabetes educator, author, and marriage and family therapist in Miami Beach, Fla., said that patients with low diabetes self-esteem are classified as those who doubt their ability to care for their diabetes or feel pessimistic about completing self-care tasks.

This poor self-esteem could result when patients become overwhelmed when their attempts to control their diabetes continue to fail. Negative comments from health care providers, family and/or friends, and the chronic stigma attached to the disease can all have a negative impact on a patient’s self-esteem, according to Roszler.

According to Roszler’s presentation, the poor self-esteem can be caused by:

  • Complications with diabetes;
  • Symptom visibility, such as blood glucose swings, numbness, fatigue, hypoglycemia;
  • Self-care tasks which are too difficult;
  • Pre-existing poor self-esteem;
  • Depression; and
  • Guilt.

Self-esteem can be raised by family, individual or group therapy. Roszler suggested a systemic therapy, with an emphasis on strength-based counseling approaches like narrative therapy, solution-focused therapy, medical family therapy, cognitive-behavioral therapy, experimental family therapy, psychoanalytic family therapy, structural family therapy and strategic family therapy.

Roszler said letting patients know that others share the same difficult issues they face often helps patients feel less alone, less “broken,” and begin to feel more hopeful.

For more information:

Roszler J. #W04. Presented at: The American Association of Diabetes Educators 2012 Annual Meeting & Exhibition; August 1-4, 2012; Indianapolis.

Source: Endocrine Today.