JACK D. WAHLEN, M.D. NOVEMBER 2, 2011. Pathophysiology of diabetes Type I diabetes insulin amylin...

JACK D. WAHLEN, M.D.

NOVEMBER 2, 2011

Pathophysiology of diabetes• Type I diabetes insulin amylinType II diabetes insulin insulin resistance fat metabolism increased hepatic glucose production gluconeogenisis and glycogenolysis

SecretagoguesSulfonylureas

Maglitinides

Biguanides (Metformin)Metformin

| activates mTORC AMPK p53/p21 inhibition (antitumor

gene) | | inhibits cancer inhibits fatty cell growth acid synthesis (breast, ovarian & prostate

cancer)

Metformin & Human Malignancy11,876 Type II DM followed 8 years. Metformin < O.R of cancer 0.79 compared to all

treatments. Duration of Rx & # of Rx filled > benefit.

10,309 Type II DM followed 5 years. Cancer mortality 1/3 less on metformin. Greater

reduction versus secretagogue or insulin.8,000 followed, 50% had Type II DM Metformin Comparator cancer 7.3 11.6 death 3.0 6.1

Women S/P Surgery for Breast Cancer

On preventive Rx. Those on metformin had a 42% lower rate of recurrance.

Those on metformin had a 3 x higher “complete response” to non-adjuvant chemotherapy.

In a randomized study metformin decreased cancer development in patients with precancerous colorectal lesions.

TZD’S Thiazolidinediones (Avandia-Actos)Nuclear regulator that change levels of ~80

genes

Present status

More specific TZD’s?

InsulinShort acting inhaled ultra rapidLong acting Concentrated Glargine Decgludec others• Combo’s basal + GLP-1

Transporters across cell membranesChannels – openings that facilitate diffusion,

hydrophillic or phobic depending on what the channel allows across the membrane. Much faster but less specific than carriers.

Carriers – transporter alters it’s configuration, allowing transmembrane transport. Slower but specific for dimensional structure can be a uniporter, symporter, or antiporter.

Sodium Glucose Luminal Transporters A symport carrier that cotransports

glucose/galactose and sodium across cell membranes.

SGLT-2 reabsorbs ~ about 90% of filtered glucose in the proximal tubule of the kidney.

Low affinity, high capacity.

SGLT-1 absorbs glucose from the intestinal lumen and 5-10% of filtered glucose in the renal tubule.

High affinity, low capacity. Also present in brain, muscle, liver and lung. Levels markedly higher in diabetic humans.

SGLT-2 InhibitorsDapaglofozin finished phase 3 trials – delayed by

FDA due to question of bladder cancer. Increased glucosuria, naturesis, and mild decrease in BP. No hypoglycemia Weight loss, several times more than

metformin related to caloric loss in urine. Minor increase in UTI and vaginitis• 2 or 3 SGLT-2 drugs in phase 2 and 3

development.

SGLT 1 and 2 InhibitorsInhibits intestinal glucose uptake and

reabsorption of glucose in the kidney.Questionable benefit and safety compared to

SGLT-2 specific drugs.

Hepatic Glucose ProductionGlucagon nonsuppression in post prandial state

in Type II diabetics accounts for much of blood glucose in the post prandial state.

Antiglucagon antibody improves glycemia in diabetic animals.

Peptide glucagon antagonists lower glucose in diabetic animals.

Small molecule glucagon antagonist improves glucose in diabetic animals. One oral antagonist improved glycemia in diabetic humans.

Questions persist as to alpha cell hyperplasia.

Direct inhibition of Hepatic Glucose Output

Inhibitors or activators of hepatic glycogen production or breakdown are being studied. Some are limited by similar effects in muscle. X-ray crystallography has illucidated 3D structure and is leading to rapid progress of drug design.

Drugs affecting glucose 6 phosphatase, fructose 1,6 bisphosphatase phosphofructokinase 1&2, glucokinase, glycogensynthase and pyruvate kinase are presently under investigation.

Liver associated protein phosphatase stimulates glycogen breakdown in the liver by stimulating glycogen phosphorylase. Inhibition of this liver associated protein will slow breakdown of glycogen in the liver. It has been shown to lower glucose in diabetic mice. There was no accumulation of glycogen in the liver. Mice lost more weight with prolonged fasting and also had lower blood sugar levels.

Glucagon InhibitorsGlucagon neutralizing antibodies improved

glycemia in diabetic animals. Peptide glucagon antagonists improve

glycemia in diabetic animals.Small molecule glucagon antagonists given

orally have improved glycemia in diabetic humans and animals.

Glucocorticoid receptor antagonistsRU486-nonselective GR antagonist

Has antidiabetic effects in humans

Used as an abortifacient due to progesterone

receptor antagonism.

Activates pituitary adrenal axis and leads to adrenal

hyperplasia.NC3327-blocks hepatic gluconeogenesis but not

some of the anti-inflammatory corticoid pathways. It is a non-steroidal small molecule.

Abbott acid 14-a very selective GR antagonist specific for liver and does not activate the HPA axis. It lowers blood glucose, cholesterol, free fatty acids and decreases weight gain in ob/ob diabetic mice.

11 Beta-hydroxysteroid dehydrogenase Type I & II (11B-HSD I & II) Cortisol is produced in the adrenal and by

conversion of cortisone to cortisol by IIB-HDS-I in various tissues.

IIB-HSD is present in liver, adipose, brain, and placenta. The Metabolic Syndrome and Cushings Syndrome (excess cortisol) share many features. Mouse phenotypes with increased adipocite IIB-HSD

activity appear to have the Metabolic Syndrome. Inhibitors of IIB-HSD-I may be of benefit in treating obesity, Metabolic Syndrome, and diabetes.

IIB-HSD-I, Obesity, & Insulin ResistanceOb/ob mice and zucker obese rats have decreased

hepatic and increased adipose IIB-HSD-I activity.In humans obesity and BMI correlates with

decreased hepatic and increased adipose IIB-HSD-I activity.

In monozygotic twins with intrapair difference in BMI of 3.8 the adipose IIB-HSD-I level is higher in the obese twin.

Selective overexpression of IIB-HSD-I in animals leads to central obesity, hypertension, low HDL, high triglyceride, insulin resistance, and glucose intolerance.

IIB-HSD-I deficient mice have improved glucose tolerance, elevated HDL, and decreased TG despite activation of the HPA axis.

Liver IIB-HSD-I is elevated in alcoholic liver disease and HIV patients on HAART who have pseudo-cushings with insulin resistance and hypertriglyceridemia.

11B-HSD-1 Inhibitors BVT2733-lowers blood glucose in ob/ob diabetic

mice.544- in diet induced diabetic mice leads to

decreased weight, blood sugar, abdominal fat, insulin, triglyceride, and cholesterol. It also decreased aortic plaque area and cholesterol content in apoE k/o mice.

Rosiglitazone decreases hepatifc 11B-HSD-1 activity in obese humans.

CBX- a nonselective 11B-HSD-l inhibitor improved cognitive function in elderly diabetic males and was well tolerated in 60 patients.

INCB13739

Phase 2a-Obese Type 2 dm treated for 4 weeks had

decreased FBS, decreased glucose production, and

increased glucose disposal.

Phase 2b-302 Type II diabetics poorly controlled on

Metformin treated for 12 weeks had decreased

HBA1c, FBG, Homa-IR, body weight and beneficial

lipid changes. ACTH levels were elevated,

suggesting activation of the HPA axis.

AmylinAmylin and analogs are being studied alone

and in combination with other hormones and peptides for weight loss. It appears significant potency for weight loss has been achieved but little data has been released.