Insulin and Non Insulin Treatments of Diabetes Mellitus

Orla Mahony

March 2012

Non-insulin treatments

Sulfonylureas Biguanides Chromium and vanadium Acarbose Incretinmimetics Amylin

Sulfonylureas (Glipizide)

Enhance insulin secretion Bind to the KATP channel on ß cell Glipizide in 50 diabetic cats; Feldman 1997 Improvement in 30% of new DM cats Side effects; hypoglycemia, vomiting, inc LE’s and icterus

(<15%) Recommend for owners unable to give insulin, or for cats with

intermittent transient DM or for cats exquisitely sensitive to insulin

Glipizide may increase amyloid deposition,Hoenig et al, 2000

Sperling M. N Engl J Med 2006;355:507-510

Regulation of Insulin Secretion

Gloyn A et al. N Engl J Med 2004;350:1838-1849

Schematic Representation of the Pancreatic Beta Cell, Illustrating the Role of the ATP-Sensitive Potassium (KATP) Channel in Insulin Secretion

Biguanides (Metformin/Glucophage)

Increases translocation of GLUT 1 & 4 transporters in different types of cells

Inhibits hepatic gluconeogenesis and glycogenolysis Increases muscle glucose metabolism by enhancing muscle

insulin sensitivity Does not stimulate insulin secretion (no hypoglycemia) Can rarely cause (fatal) lactic acidosis by stimulating intestinal

conversion of glucose to lactate Decreased hepatic synthesis of VLDL Metformin & sulfonylureas produce similar results Weight gain rare with metformin

Metformin in Cats

Nelson et al, JVIM 2004 Study involved normal and diabetic cats Disappointing results, 3 failed to respond and

1 died Death undetermined Side effects included lethargy, inappetence,

vomiting, and weight loss

Chromium and Vanadium

Transition-metals Activate glucose metabolism within the cell Insulin sensitizers Chromium is an essential cofactor for insulin function and

chromium deficiency results in insulin resistance Schachter et al 2001; Chromium had no effect in diabetic dogs Appleton DJ et al 2002; Improved glucose tolerance in normal

weight, healthy cats given chromium Greco D states low doses of vanadium (0.2mg/kg/day)

lowers glucose and fructosamine in early T2DM catsTransient anorexiaLong term accumulation could lead to CRF (1 cat)

Acarbose

Complex oligosaccharide of microbial origin Competitively inhibits α-glucosidases in GIT Acarbose improved glucose control in 6 diabetic

dogs but ⅓rd had diarrhea and weight loss

Nelson et al 2000 Diabetic cats fed a low CHO diet had a similar

response to cats on low CHO diet and acarbose Mazzaferro et al JFMS 2003

Incretin Hormones

Incretins– GIP, glucose-dependent insulinotropic

polypeptide– GLP-1, glucagon like peptide 1

Incretin effect

The incretin effect is the increased insulin secretion which occurs with food ingestion as a result of release of incretin hormones, primarily GIP and GLP-1.

Oral GTT versus i/v GTT

• Secreted by K cells of duodenum in response to food

• Primary action is stimulation of glucose-dependent insulin secretion

• May stimulate β cell proliferation and inhibit apoptosis

• Inactivated by Dipeptidyl-peptidase IV (T½ 7 mins)

GIP Glucose-dependent insulinotropic polypeptide

Glucagon-like peptide 1 GLP-1Glucagon-like peptide 1 GLP-1

Produced by L-cells (primarily distal SI) Secreted in response to nutrient ingestion Stimulates glucose-dependent insulin secretion

(via G protein coupled R, ↑ cAMP, ↑ iCa, exocytosis)

Effect on insulin secretion may also be via autonomic nerves

βcell proliferation and neogenesis in rodents Inhibits apoptosis in human tissue cultures Extensively metabolized by the enzyme DPP-4

Other Actions of GLP-1 Other Actions of GLP-1

Inhibits glucagon secretion Delays gastric emptying Reduces food intake Cardioprotective effects Renal protective effects Modulatory role in HPit axis?

Incretins in cats

GLP-1 secretion is stimulated by glucose, amino acids and lipids

K and L cells throughout small and large GI Potentiation of insulin secretion is minimal

with oral glucose and is mediated by GLP-1, not GIP

GIP secretion is stimulated by amino acids and lipids

DPP-4 / CD26

Serine protease Degrades GLP-1 and GIP Ubiquitous in tissues and blood Only 15% active form reaches systemic

circulation, therefore need to measure active and inactive forms (total) to evaluate GLP -1 secretion

GIP more than GLP also degraded renally

Loss of the incretin effect in T2DM and Loss of the incretin effect in T2DM and obesityobesity

Loss of β cell response to GIP Decreased secretion of GLP-1 (2° to DM) Impaired β cell sensitivity to GLP-1 Glucose stimulated GLP-1 concs. higher in

lean vs obese cats, Hoenig 2010

Implications

Treatment with GIP unhelpful Treatment with native GLP-1 unhelpful (T1/2

2 mins) Treatment with GLP-1 analogs Dipeptidyl peptidase-4 inhibitors

GLP-1 mimetics

Exenatide (Byetta), synthetic exendin-4 8 hr DOA, biologic effects up to 15 hrs Restores early insulin response As effective as insulin glargine but fewer side effects One report of pancreatitis Antibody formation common Promotes beta cell regeneration and differentiation

(rats)

Amylin/Pramlintide

Synthetic analog of amylin (IAPP) that does not form amyloid

Approved for treatment of T1 and T2 DM 2005 Slows gastric emptying Suppresses post prandial hyperglycemia Decreases postprandial hyperglucagonemia Improves glycosylated Hb concn

Weight loss (desirable) Side effects include nausea and hypoglycemia

Amylin in cats

Amylin reduces glucagon in normal cats Vet Journal 2009, Furrer et al Study used rat amylin, and showed mild

decreases in glucagon following arginine, glucose and meal stimulation.

Short acting May be more beneficial in diabetic cats

Insulins

Humulin NPH U100 Insulin glargine/Lantus U100 Detemir U100 PZI U40 Porcine Lente U40

All mammalian insulin is similar 51 AA’s in 2 polypeptide chains 21 AA A-chain 30 AA B chain

Formulation

Short-acting Intermediate-acting Long-acting Sometimes mixed together Do not mix glargine or Zn insulins

with other insulins

Lentes (semilente, lente, ultralente) all have _____ to delay absorption

NPH has _____ to delay absorption PZI has _____ and _____ to delay absorption 1 unit of insulin = 36 mcg of insulin Use U40 syringes with U40 insulin (40 IU/ml) Vetsulin (porcine lente) and PZI are U40 (40 IU/ml)

insulins

½ unit scale syringes are available (diabetes care, 31g, 30u short needle)

Vial syringe guides Syringe magnifiers

Keith et al showed drawing up 1-2 unit doses inaccurate with syringes

Humulin NPH U100 / Isophane (neutral protamine Hagedorn)

Contains fish protein, protamine, to delay absorption Intermediate insulin Recommended for dogs Give BID Goeders et al 1987; dogs

Time for NPH to return to baseline; 8 hrs Wallace et al 1990; cats

Peak insulin concentraton 1.6 hrs, DOA 7.7 hrs.

Humulin NPH in diabetic dogsPalm et al JVIM 2009;23:50-55

• 10 well controlled DM dogs, <1U/kg bid, fed high fiber diets (wd 7, euk wt control 3, nutro wt control)

• BG and insulin measured q 30mins for 2hrs, then q 2hrs for up to 10hrs

• Insulin DOA 4-10hrs (T0 bg to time for bg to reach 70% of baseline), 4 dogs ≥ 10 hrs

• Mean % of insulin-induced glucose suppression 50%

• Post-prandial hyperglycemia in 5 dogs, resolved within 2.2hrs

Insulin Glargine/Lantus

Human recombinant insulin with AA substitutions and additions

Shift in isoelectric pt.,soluble at pH 4 Insulin precipitates into hexamers at

interstitial pH of 7.4 Hexamers slowly form active insulin

monomers Gradual onset, long duration

Insulin glargine/Lantus

Insulin Glargine/Lantus

Glucose nadir healthy cats; glargine (14 hrs), PZI (biphasic 4, 14 hrs), lente (5 hrs) Marshall et al, J vet Pharmacol Therap 2008

SID not inferior to bid in normal cats, Marshall 08 BG suppressed @ 24 hrs in 1/2 of sid or bid cats Higher remission rate with glargine (8/8) vs PZI (3/8)

vs lente (2/8) newly dx diabetics, dm canned dietMarshall et al, JFMS 2009

Glargine SID is as effective as lente BID Weaver et al, JVIM 2006

Use of insulin glargine in dogs with DM Fracassi Vet Rec 2012

12 dogs, 9 new diabetics, 3 tx with vetsulin 3 intact females (spayed within 3 wks) Glargine; 0.27 U/kg (0.18-0.53) at start and

0.6 U/kg (0.11-1.07) at end Nadir varied (0-12), 6, 8, 10 hrs on average BG<90 in 18% of curves, no clinical hypogly Varied diet

BGCs done before, 1, 2, 4, 8, 12, 24 weeks 12 hr curves, dog usually fed and inj. @ hosp 58% good control (mean bg < 230) 33% moderate control (mean bg 230-300) 1% poor control (mean bg >300) Fructosamine (good 25%, moderate 58%,

poor 17%)

Discussion

Results similar to NPH and vetsulin studies although vetsulin study stated 75% good control

No clinical hypoglycemia Clear nadir (unlike in people, peakless) but

unpredictable May have needed 24 hr curve to determine

nadir

Insulin Detemir/Levemir®U100 Insulin

Approved in US 2006 Long-acting,synthetic insulin analogue Similar to glargine Slow release due to formation of hexamers as well as

binding to albumin at the injection site and in the circulation( inc. availability to liver w fenestrated vessels)

More consistent glucose lowering than with lantus Reduced risk of hypoglycemia? 2 studies of use in cats Max dose 30% lower than lantus, rarely > 4U

Detemir is acetylated with myristic acid(saturated FA found in dairy products), allowing hexamers to form at a neutral pH, and importantly allowing the insulin to bind to albumin, resulting in a very slow, smooth delivery of insulin such that once daily administration is all that is needed in people

ProZinc™

Protamine zinc recombinant-human insulin U40 insulin, use with U40 syringes Preliminary study of PZIR for the Tx of DM in

cats Vet Ther 2009;10:24-28– 50 cats, switched from PZI VET to PZIR same dose

and interval, no significant differences in wt, fruct days 15, 30 compared to day 0.

Field safety and efficacy of PZIR bid for Tx of DM in cats JVIM 2009;23:787-793

• 133 cats, 13 previously diagnosed• 9hr bg curve done day 0, 7, 14, 30, 45. Fruct

done day 0, 14, 30, 45• Hypoglycemia (<80) detected in 64% of cats• Clinical signs in 2, possibly 26 other episodes• On day 45, 34% of cats had low glu nadir, mean

bg or fruct on day 45, some were probably going into remission

• Bid admin, nadir 5-7, bg increasing by 9hrs

PZI and Dogs?

Pharmacokinetics and Pharmacodynamics of Glargine, Beef-Pork PZI & Pork Lente Insulin in Healthy Dogs Stenner ACVIM abs 2004

Onset of Action; lente (0.6 hr), PZI (3 hrs) Glargine (2.2 hrs) Glucose Nadir; lente (2.4 hrs) glargine (5.7 hrs) PZI (6.4 hrs) DOA lente (10 hrs) glargine (13 hrs), PZI (19 hrs) Peak insulin; lente (1.2 hrs), glargine (0.5-6 hr), PZI (0.5 hr) Glargine had no glucose lowering effect in 2/9 dogs Glargine unpredictable in dogs PZI glucose lowering effect in 9/9 dogs but Ab’s to beef insulin

a potential concern

Efficacy of rhPZI in dogs with DMMaggiore et al JVIM 2012

6 new diabetics, 11 previous diabetics 10 hr bg curve day 7, 14, 30, 60 Fructosamine, spec cPL 0.25-0.5 U/kg initial dose Goal; bg between 80-300, nadir 80-150

Results

LBG10h 80-150 n= 4, >200 n=11, <80 n=2 No significant change betw day 1 and 60 LBG10h >200 in 42 of 68 bg curves

LBG10hr occurred 2-12 hrs post inj, and in 54% was at start or end of curve

7 hypoglycemic events (3 clinical, 4 nonclinical during curves)

Results

MBG 299±115 vs 457±38 MBG decreased in 16 dogs Fructosamine 478±83, vs 557±104 Fruct decreased in 11/17 dogs PuPd improved in 14Body wt stable or

increased in 16

Inconsistency in BG concs from day to day

Prolonged duration of rhPZI effect Somogyi response Pharmacokinetic variability of rhPZI Once daily administration? High dose requirements Starting dose of 0.5U/kg Median end dose of 1U/kg (0.4-1.5)

Porcine Lente Insulin (Vetsulin) U40

40 IU/ml Mixed insulin Zn suspension 30% amorphous semilente rapidly absorbed 70% crystalline Zn ultralente slowly absorbed Intermediate insulin Licensed for use in dogs Less potent than NPH but longer acting

Vetsulin continued

DOA 14 to 24 hrs Many dogs have 2 peaks (4, 11 hrs) of insulin

activity (Graham et al, JSAP 1997) In some dogs earlier peak is largest Dose ¼ to ½ u/kg SQ BID U40; more accurate dosing in small dogs Administer BID (Munroe et al, JVIM 2005)

(Horn et al, Aust Vet J 2001)

Vetsulin in Cats

Parmacology of Vetsulin in diabetic cats Martin et al, JFMS 2001

Time to peak insulin 2 hrs Time to glucose nadir 4 hrs Time for insulin concentration to return to baseline – 8 hrs Give BID (may even need TID) Similar pharmacological properties to beef-pork NPH Shorter DOA compared with Humulin and beef/pork UL and

beef-pork PZI Antibodies to porcine insulin possible Poor absorption possible

Amino Acid Differences between species

A8 A10 A18 B30

Dog Thr Ile Asn Ala

Pig Thr Ile Asn Ala

Human Thr Ile Asn Thr

Cow Ala Val Asn Ala

Cat Ala Val His Ala

Feldman & Nelson 3rd Ed p496