Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

Click on title for pdf download...

Should diabetes patients be on these new incretin drugs long term?

Gastroenterology. 2011 Jul;141(1):150-6. Epub 2011 Feb 18.


Abstract


BACKGROUND & AIMS: Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.



METHODS:

• We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.
• The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.

RESULTS:

• Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)).
• Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)).
• All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).

CONCLUSIONS: These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Caloric Restrictions in the news

Here is a story in the Los Angeles time describing the study of caloric restriction in Monkeys. If over-nutrition is the problem, how do we counteract this.

read more....

Caloric restriction effects?

Here is an interesting article documenting the cellular effects of primates on CR(Caloric Restriction) for 4 years. It appears they have more insulin sensitivity. But this was not due to the increased production of the receptors or a decrease in processing.

In summary, if you want to live longer and have more insulin sensitivity....Eat Less.

Read further here....
Diabetes July 2009 58:1488-1498; published ahead of print March 31, 2009,

Is more of the right fat the answer?

A study in the journal Diabetes examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet.

The concluded that:

• Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse.
  
• The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.

to read more....

HDL Exposing the complexity

I had a physician argue that his diabetes patient with an HDL of 70 was safe from cardiovascular risks. He of course did know of the inner complexities of the HDL. I explained to him that in diabetes patients, a HDL may actually to proatherogenic. HDL functions by promoting cholesterol efflux and inhibiting inflammation. But, if the HDL is overloaded, such as the patient with the HDL of 70, it can actually be pro-inflammatory.

A good editorial to read....

ADA Accord follow-up

PTU dangerous?

June 3, 2009 — The US Food and Drug Administration (FDA) issued a safety alert today about the risk for serious liver damage, including liver failure, or death with propylthiouracil (PTU) compared with methimazole. Both agents are approved for the treatment of hyperthyroidism associated with Graves' disease.

“Health care professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves’ disease," Amy Egan, MD, deputy director for safety, Division of Metabolism and Endocrinology Products, in the FDA’s Center for Drug Evaluation and Research, said in a news release. "If PTU therapy is chosen, the patient should be closely monitored for symptoms and signs of liver injury, especially during the first six months after initiating therapy.”

Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters

Bromocriptine reduced plasma concentration of insulin throughout the day, especially at light onset, by 78% without change in baseline glucose level and markedly decreased steady state plasma glucose (by 40%) during a continuous infusion of insulin and glucose. It also reduced the nocturnal plasma concentration of prolactin by 90%, cortisol by 70%, and thyroid hormones (thyroxine and triiodothyronine) by 50% and dramatically altered the circadian profiles of these hormones and insulin.

click here to read more....

Bromocriptine and diabetes

Diabetes Care. 2000 Aug;23(8):1154-61. Links

Bromocriptine: a novel approach to the treatment of type 2 diabetes.

OBJECTIVE:

• In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations.
• Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes.
• We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS:
There were 22 obese subjects with type 2 diabetes
randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study.
Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements.
Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment.
Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment.

RESULTS:
No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects.
Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant.
The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group.
During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group.

CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.

Secular Trends in the Presentation and Management of Functioning Insulinoma at the Mayo Clinic, 1987–2007

The cohort of functioning insulinomas consisted of 237 patients (135 women, 57%), aged 50, 17–86 yr (median, range) with a body mass index of 27.8, 17.5–53.8 kg/m2 and 1, 1–14 tumors per patient. Malignant tumors occurred in 10 patients (4%).

You don't have to be fat to suspect insulinoma.

This is an excellent mayo reports of their series.

New guidelines alert!

Let's get some opinions on the new guidelines.

Here is the rehash of the algorithm. It appears that most people are treated in the tiered pathyway.

NICE-SUGAR, Mean endocrinologist?

Intensive versus Conventional Glucose Control in Critically Ill Patients

The NICE-SUGAR Study Investigators

Abstract PDF Supplementary Material Editorial by Inzucchi, S. E. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited

ABSTRACT

Background

The optimal target range for blood glucose in critically ill patients remains unclear.

Methods

• Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter).
• We defined the primary end point as death from any cause within 90 days after randomization.

Results

• Of the 6104 patients who underwent randomization,
  
• 3054 were assigned to undergo intensive control and
  
• 3050 to undergo conventional control; data with regard to the
  
• primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).

Conclusions
In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987 [ClinicalTrials.gov] .)

Gastric Bypass and diabetes

Macronutrient important in the long run for weight loss?

Sacks FM, Bray GA, Carey VJ, et al. Comparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates. N Engl J Med. 2009;360(9):859-873. Available at: http://content.nejm.org/cgi/content/abstract/360/9/859

Background

The possible advantage for weight loss of a diet that emphasizes protein, fat, or carbohydrates has not been established, and there are few studies that extend beyond 1 year.

Methods

We randomly assigned 811 overweight adults to one of four diets; the targeted percentages of energy derived from fat, protein, and carbohydrates in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. The diets consisted of similar foods and met guidelines for cardiovascular health. The participants were offered group and individual instructional sessions for 2 years. The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content.

Results

• At 6 months, participants assigned to each diet had lost an average of 6 kg, which represented 7% of their initial weight; they began to regain weight after 12 months.
  
• By 2 years, weight loss remained similar in those who were assigned to a diet with 15% protein and those assigned to a diet with 25% protein (3.0 and 3.6 kg, respectively); in those assigned to a diet with 20% fat and those assigned to a diet with 40% fat (3.3 kg for both groups); and in those assigned to a diet with 65% carbohydrates and those assigned to a diet with 35% carbohydrates (2.9 and 3.4 kg, respectively) (P>0.20 for all comparisons).
• Among the 80% of participants who completed the trial, the average weight loss was 4 kg; 14 to 15% of the participants had a reduction of at least 10% of their initial body weight. Satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar for all diets; attendance was strongly associated with weight loss (0.2 kg per session attended).
  
• The diets improved lipid-related risk factors and fasting insulin levels.

Conclusions

Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize.

Critical appraisal of the literature

How to Use an Article About Therapy or Prevention

Gordon H. Guyatt, David Sackett, Deborah J. Cook, for the Evidence Based Medicine Working Group

Based on the Users' Guides to Evidence-based Medicine and reproduced with permission from JAMA. (1993;270(21):2598-2601) and (1994;271(1):59-63). Copyright 1995, American Medical Association.

• Clinical Scenario
• The Search
• Introduction
• I. Are the results of this article valid
• II. What were the results
• III. Will the results help me in caring for my patients
• Resolution of the Scenario
• Conclusion
• References

read more....

Site called netting the evidence has a very good summary of evidence based medicine.

Byetta extend life?

Lilly Diabetes Drug Shows a Life-Extending Promise
By ALEX BERENSON

Can Byetta, an injectable drug that lowers blood sugar, really help people with diabetes to live longer?

Possibly, according to the results of a major clinical trial presented at the American Diabetes Association annual conference. In the trial, called Accord, patients with Type 2 diabetes were prescribed Byetta or any of several other diabetes medicines. Patients who took Byetta had a much lower chance of dying, about 75 percent lower, than those who took any other drug.

The finding, presented in June, has generated a stir among diabetes researchers, although so far it has attracted little public notice. Neither Eli Lilly or Amylin, the companies that jointly market Byetta, is publicizing the findings, in part because no one is sure whether the reduction in the death rate is real or a chance finding. Only about 825 patients in the 10,000-patient Accord trial took Byetta, and those who did were likelier to be healthier than other patients.

Read more....

Hypoxia in hypertrophic adipocytes to trigger inflammation

In this issue of Diabetes, two articles highlight the emergence of inflammation's contribution to insulin resistance and to chronic diseases in humans. The common feature in each article is the inflammation–obesity–insulin resistance connection, but each article approaches the investigation from a completely different perspective.

1. Specifically, the study of Ortega Martinez de Victoria et al. (1) comments on factors related to macrophage activation in adipocytes as a source for cytokines for systemic inflammatory effects.

2. In contrast, the study of Haus et al. (2) provides data on systemic effects resulting from inflammatory activation, namely, the relationship of cytokines with circulating lipid intermediates.

The precise physiological events leading to initiation of the inflammatory response in obesity remain incompletely understood.

1. However, one emerging hypothesis, as recently evaluated by Regazzetti et al. (10), envisions hypoxia as a novel mechanism participating in insulin resistance in adipose tissue of obese patients. It has been suggested that hypertrophic adipocytes become hypoperfused, creating regional areas of microhypoxia leading to increased expression of hypoxia-inducible factor-1.

click here to read more.

HDL can be bad?

Curr Opin Lipidol. 2007 Aug;18(4):427-34.

The paradox of dysfunctional high-density lipoprotein.
Ansell BJ, Fonarow GC, Fogelman AM.

Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. bansell@mednet.ucla.edu

PURPOSE OF REVIEW: This review addresses how, in atherosclerosis or systemic inflammation, HDL can lose its usual atheroprotective characteristics and even paradoxically assume proinflammatory properties.
RECENT FINDINGS: Specific chemical and structural changes within HDL particles can impede reverse cholesterol transport, enhance oxidation of LDL, and increase vascular inflammation. HDL may be viewed as a shuttle that can be either anti-inflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. Some therapeutic approaches that reduce coronary risk, such as statins and therapeutic lifestyle changes, can favorably moderate the characteristics of proinflammatory HDL. In addition, apolipoprotein A-I mimetic peptides and other compounds that target functional aspects of HDL may offer novel approaches to reduction in cardiovascular risk.

SUMMARY: Current data suggest that under some conditions HDL can become dysfunctional and even proinflammatory, but this characterization can change with resolution of systemic inflammation or use of certain treatments.

Nobel prize give a cheap tx for CAD.

Can GLP-1 really be classified as an incretin?

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

In this study Nauk reveals some interesting things:
1. the predominant GLP-1 effect in the lowering of blood sugar comes from the lowering of GI motility and not the stimulation of insulin.
2. GLP-1 physiologically doesn't cause an increase in insulin. Rather, since it has such a strong effect of reducing GI motility, it actually lowers the postprandial insulin level.

read more....